Репозиторий Университета

© 2019, The Author(s). Objectives: This study was aimed to assess hemostatic disturbances in female patients with established rheumatoid arthritis (RA) in relation to menopausal status and disease activity. Method: Ninety women were included in the study, 42 patients and 48 age-matched healthy controls. There were no differences between the investigated groups regarding the presence of traditional cardiovascular risk factors. Two global hemostatic assays were employed, namely endogenous thrombin potential (ETP) and overall hemostasis potential (OHP). The parameters of the ETP assay (ETP, C-max, t-lag, t-max) and OHP assay (overall coagulation potential (OCP) and overall fibrinolytic potential (OFP)) were assessed. Moreover, the parameters of the fibrin clot (lag time, Max Abs, and slope) were measured by clot turbidity and scanning electron microscopy (SEM). Both patients and controls were divided into four subgroups according to menopause status. Results: The premenopausal controls differed significantly from all other subgroups in terms of diminished levels of ETP (p = 0.02), C-max (p = 0.01), OCP (p = 0.02), OHP (p = 0.001), and Max Abs (p = 0.008), while OFP (p = 0.0001) was increased. This tendency was not seen in the premenopausal RA patients compared with the postmenopausal RA patients. SEM images showed denser clots composed of thinner fibers in samples from RA patients. The disease activity measured by DAS28 correlated with OCP and OHP (r = 0.54; p = 0.001 and r = 0.44; p = 0.003, respectively) indicating persistent hypercoagulable condition in the whole group of RA patients. Conclusions: Our results point towards coagulation activation in premenopausal women with established RA. The patients were well characterized, which enabled assessment in a real-life setting.Key Points• Extensive assessment points towards persistent coagulation activation in premenopausal women with established rheumatoid arthritis.• Impaired thrombin generation and fibrin formation are associated with menopause in healthy women, while rheumatoid arthritis closes the gap within patients regarding menopause.• Fibrin morphology is unfavorably altered and fibrinolysis is decreased in patients with established rheumatoid arthritis.• Increased activity of thrombin activatable fibrinolysis inhibitor (TAFI) may contribute to impaired fibrinolysis in patients with rheumatoid arthritis.

© 2019, International League of Associations for Rheumatology (ILAR). Background: Patients with rheumatoid arthritis (RA) are at a high risk for life-threatening conditions requiring admission to the intensive care unit (ICU), but the data regarding the outcomes of these patients is limited. The present study investigated the clinical characteristics and outcomes of RA patients admitted to an ICU. Methods: This retrospective cohort study included RA patients admitted to the general ICU of the Sheba Medical Center during 2002–2018. The main outcome was 30-day mortality. Using Student’s t test, χ2, and multivariable analyses, we compared the demographic, clinical, and laboratory parameters of the survivors and the non-survivors. Figures with p value < 0.05 were considered statistically significant. Results: Forty-three RA patients were admitted to the ICU during the study period (mean age, 64.0 ± 13.1 years; 74.4% female). The leading causes of ICU admission were infection (72.1%), respiratory failure (72.1%), renal failure (60.5%), and septic shock (55.8%). The 30-day mortality rate was 34.9%, with infection (9/15, 60%) as the most frequent cause. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were 19.7 ± 12.5 and 7.0 ± 4.5, respectively. Multivariable analysis showed that heart failure (p = 0.023), liver failure (p = 0.012), SOFA score (p = 0.007), and vasopressor treatment in ICU (p = 0.039) were significantly associated with overall mortality. SOFA score was linked with overall mortality (area under the curve (AUC) = 0.781 ± 0.085, p = 0.003) and mortality from respiratory failure (AUC = 0.861 ± 0.075, p = 0.002), while APACHE II score was only correlated with mortality from infection (AUC = 0.735 ± 0.082, p = 0.032). Conclusions: Our study demonstrated a relatively high mortality rate among RA patients who were admitted to the general ICU. RA patients with risk factors such as heart failure, liver failure, elevated SOFA score, and vasopressor treatment in ICU should be promptly identified and treated accordingly.Key Points• The 30-day mortality rate of patients with RA that were admitted to the general ICU of a tertiary hospital was 34.9%.• The most common causes of ICU admission among patients with RA were infections and respiratory failure. Infections were the most common cause of death among these patients.• Patients with RA that present to the ICU with heart failure, liver failure, elevated SOFA score, and/or require vasopressor treatment in ICU should be promptly identified and treated accordingly.

© 2019, International League of Associations for Rheumatology (ILAR). Introduction: Long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) have been reported to reduce platelet aggregation. Our aim was to prospectively assess the potential influence of different supplementation omega-3 PUFA on the antiplatelet effects in rheumatoid arthritis (RA) patients. Methods: The study included 60 patients with RA at the Department of Rheumatology, Clinical Center Kragujevac. Patients were divided into three groups depending on who used concentrated fish oil only or concentrated fish oil in combination with evening primrose oil or control group without supplementation in a period of 3 months. Platelet aggregation was measured using the multiplate analyzer and expressed through the value of adenosine diphosphate (ADP) test, aranchidonic acid–induced aggregation (ASPI) test, thrombin receptor–activating peptide (TRAP) test (to assess baseline platelet aggregation), and the ratio of ADP/TRAP and ASPI/TRAP representing the degree of inhibition of platelet aggregation compared to the basal value. The platelet function analysis in whole blood was performed 18–24 h before starting supplementation and after 90 days. Considerations were taken in the representation of demographic, clinical characteristics, and laboratory parameters between the groups. Results: Patients who used concentrated fish oil only had a significantly lower value of the ratio of ADP/TRAP (0.68 ± 0.20) compared to patients without supplementation (0.83 ± 0.12; p = 0.008), while there was no statistically significant difference in values of other laboratory parameters of platelet function between other groups. Conclusions: Co-administration of supplementation-concentrated fish oil may reduce platelet aggregation in adults with RA. Key Points: • Omega-3 PUFAs are essential for health and are known to possess anti-inflammatory properties, improving cardiovascular health as well as benefiting inflammatory diseases. • In this paper, we report on anti-aggregation effects n-3 PUFAs and ɤ-linolenic acid in RA. • The risk of cardiovascular morbidity and mortality is increased in RA, and dietary supplementation of n-3 PUFA may have preventive potential for the cardiovascular management in rheumatoid arthritis.

© 2018, SICOT aisbl. Objective: To investigate the effect of knee arthroscopic synovectomy (AS) on the disease activity, quality-of-life (QoL), and the functional status of patients with rheumatoid arthritis (RA). Materials and methods: A retrospective analysis was conducted on the outcomes of AS performed on 138 RA patients; pre-surgery assessments were done using Disease Activity score (DAS 28) and Routine Assessment of Patient Index Data З (RAPID-3) on а multidimensional health-assessment questionnaire for disease activity, EuroQol-5D (EQ-5D) and the Short-Form Medical Outcomes Study (SF-36) for quality of life, and the Health Assessment Questionnaire (HAQ) for functional status. The pain response to SA was measured by а visual analogue score (VAS) and the Knee Society Score (KSS). Results: All parameters assessed in the study showed significant positive changes: the activity of the disease decreased, and patients’ functional status and QoL improved. Conclusion: AS is effective treatment for recurrent synovitis of the knee in RA patients. This technique improves the functional status of patients and their quality of life and reduces the activity of the disease.

© 2018 Tong, Lönnblom, Yau, Nandakumar, Liang, Ge, Viljanen, Li, Bãlan, Klareskog, Chagin, Gjertsson, Kihlberg, Zhao and Holmdahl. Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the a3(XI) chain is identical to the a1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures. Methods: Mice expressing the susceptible immune response gene Aq were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments. Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of a3(XI) or a1(II) chain. The L10D9 antibody binds cartilage in vivo and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis. Conclusion: CXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response.

© 2018 Universiteit Gent. All Rights Reserved. Due to the recent introduction of golimumab into paediatric rheumatology practice, an overview of the clinical studies of this tumour necrosis factor alpha inhibitor, most of which were conducted with adult patients with rheumatic diseases, has been presented. Clinical laboratory effects and tolerability of golimumab in the form of subcutaneous injections have been analysed for rheumatoid arthritis, psoriatic arthritis, and spondylitis. Evaluation of the efficacy and tolerability of golimumab in long-term observational studies (up to 5 years) has been discussed.

© 2018 Media Sphera Publishing Group. All rights reserved. According to modern ideas, chronic low-grade inflammation, which development is associated with uncontrolled activation of both innate and adaptive immunity, plays a fundamental role in all stages of the atherosclerotic process. The contribution of inflammation to the development of atherosclerotic vascular lesions attracts attention to the similarity of the mechanisms of immunopathogenesis of atherosclerosis and classic inflammatory rheumatic disease - rheumatoid arthritis. In the aspect of participation in the pathogenesis of atherosclerotic vascular lesions and as a promising therapeutic "target" of particular interest is interleukin-1β (IL-1β), which plays an important role in the development of many acute and chronic immunosuppressive diseases. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "Pro-atherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "proatherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. Convincing evidence for the role of inflammation in development of atherosclerosis in General and good prospects of anti-inflammatory therapy in particular obtained in a randomized placebo-controlled study called CANTOS (Canakinumab Anti-inflammatory Thrombosis Otcomes Study), which studied the effectiveness of treatment with monoclonal antibodies to IL-1β canakinumab (Novartis International AG) in patients with severe atherosclerotic vascular lesions as a new approach to secondary prevention of cardiovascular complications. The results of CÀNTOS research, as well as the experience gained in rheumatology in regard to cardiovascular effects of innovative antiinflammatory drugs, have great importance for the improvement of secondary prevention of atherosclerosis-related cardiovascular complications.

© 2018 Ima-Press Publishing House. All rights reserved. Atherosclerosis is now considered as chronic inflammatory vascular disease connected to «pathological» activation of innate and adaptive immunity, characterized by lipid deposition, leukocyte infiltration and proliferation of vascular smooth muscle cells. Subclinical (low grade) inflammation plays fundamental role at all stages of atherosclerotic process progression and determines cardiovascular catastrophes development and mortality. Proinflammatory cytokines including interleukin (IL) 1, IL6, tumor necrosis factor α (TNFα), IL17, IL18, IL27, IL33, IL37 tightly interacting within cytokine network occupy an important place among numerous mediators participating in immunopathogenesis of atherosclerosis and rheumatoid arthritis. IL1β playing an important role in the development of many acute and chronic immunoinflammatory diseases attracts particular attention. IL1β significance in the development of atherosclerosis is determined by many mechanisms including procoagulant activity, enhancement of monocytes and leucocytes adhesion to vascular endothelium, vascular smooth muscle cells growth and others. Fundamental role of inflammation in the development of atherosclerosis is well proved in investigations of anti-atherosclerotic effect of canakinumab. Randomized placebo-controlled trial CANTOS (Canakinumab ANti-inflammatory Thrombosis Otcomes Study) assessing efficacy of canakinumab as new tool for secondary prophylaxis cardiovascular complications in general population of patients with severe atherosclerotic vascular damage. CANTOS results in combination with accumulated in rheumatology data on cardiovascular effects of anti-inflammatory drugs are of great importance for personification of approach to secondary prophylaxis of caused by atherosclerosis cardiovascular complications. They also contribute to the development of inflammatory theory of atherosclerosis pathogenesis in the whole.

© 2018 Ima-Press Publishing House. All rights reserved.  The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor. Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity. Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+CD38+), and plasmablasts (CD19+CD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•10 9 /l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•10 9 /l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•10 9 /l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•10 9 /l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•10 9 /l; 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•10 9 /l to 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•10 9 /l and 0.003 [0.001; 0.007]•10 9 /l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•10 9 /l and 0.02 [0.01; 0.04]•10 9 /l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation. Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.

© 2018 Ima-Press Publishing House. All rights reserved. Objective: to determine risk factors (RFs) for venous thromboembolic events (VTE) in patients with rheumatoid arthritis (RA). Subjects and methods: The investigation enrolled 374 patients (311 women and 63 men) with a reliable diagnosis of RA who met the 2010 ACR/EULAR classification criteria. The patients' mean age was 53.7±13.6 years; the disease duration was 12.1±10.7 years. All the patients were treated at the V.A. Nasonova Research Institute of Rheumatology Clinic during the period from 2014 to 2017. A standard clinical examination of the peripheral joints was performed. RA activity was measured using DAS28. A survey was made using a questionnaire including questions on traditional RFs for VTE and RFs that might be caused by RA and its therapy. Results and discussion. VTE were recorded in 45 (12%) out of the 374 patients. Group 1 included 45 patients with VTE; Group 2 consisted of 329 patients without VTE. Multidimensional analysis showed an increased risk of developing VTE in RA under the influence of the following factors: high inflammatory activity; lower extremity varicose veins; hypercholesterolemia; and hypertension. Their weighted coefficients were 1.1, 2.5, 1.0, and 0.9, respectively. According to the obtained model (p<0.001), the risk of VTE in RA can be predicted by the following formula: Z = 1.1 • high RA activity (Yes = 1/No = 0) + 2.5 • lower extremity varicose veins (Yes = 1/No = 0) + + 1.0 • hypercholesterolemia (Yes = 1/No = 0) + 0.9 • hypertension (Yes = 1 / No = 0). Conclusion: The increased risk for VTE in RA patients determines the need for its timely assessment, by taking into account the known risk factors as both standard ones and those caused by the disease itself and its therapy. This risk assessment is necessary for the timely adequate treatment and prevention of thrombotic events in RA.

© 2018 Ima-Press Publishing House. All rights reserved. Objective: to evaluate the clinical efficacy of the rituximab biosimilar Acellbia® at a dose of 600 mg intravenously at a 2-week interval in patients with active rheumatoid arthritis (RA) 12 and 24 weeks after initiation of treatment. Subjects and methods. Examinations were made in 20 active seropositive RA patients who had not been previously treated with biological agents (BAs), but received two infusions of the rituximab biosimilar Acellbia® at a dose of 600 mg intravenously at a 2-week interval during stable therapy with methotrexate (MT) and glucocorticoids (GCs). The European League Against Rheumatism (EULAR) response criteria (Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index) and the American College of Rheumatology (ACR) criteria were used to evaluate the efficiency of Acellbia® therapy. Disease remission was identified by DAS28 and 2011 ACR/EULAR criteria. The safety profile (the frequency of all reported adverse events) corresponds to the data on the safety of rituximab (MabThera®). Results and discussion. At the time of inclusion, median DAS28 was 5.6 [4.9; 6.8], SDAI - 27.1 [23.0; 39.9], and CDAI - 26.6 [22.2; 37.0]. At week 12 after initiation of Acellbia® therapy, they decreased to 4.2 [3.24; 4.75], 14.4 [8.5; 20.7], and 13.2 [7.9; 19.0] respectively, which remained at 24-week follow-up (p<0.01). At week 12, the frequencies of ACR 20%, 50%, 70% improvements were 70, 55, and 5%; at week 24, these were 75, 45, and 15%, respectively. A good or moderate EULAR response at week 24 was observed in 25 and 60% of patients, respectively. At week 24, DAS28, SDAI, and CDAI remissions were achieved by 4 (20%), 2 (10%), and 1 (5%); low disease activity - by 4 (20%), 5 (25%), and 6 (30%) patients, respectively; high disease activity as measured by SDAI and CDAI remained in 3 (15%) patients. Two patients (10%) met the 2011 ACR/EULAR remission criteria at 24 weeks. Conclusion. The rituximab biosimilar Acellbia® 600 mg used in patients with active seropositive RA is clinically effective and comparable in the safety profile as shown in investigations of the brand-name MabThera® (F. Hoffman-La Roche Ltd., Switzerland) at a low dose (500 mg), as well as the first BA.

© 2018 Ima-Press Publishing House.All right reserved. Objective: to study changes of acute-phase reactants (erythrocyte sedimentation rate – ESR, C-reactive protein – CRP), autoantibodies (IgM/IgA rheumatoid factors – RF, anti-citrullinated protein antibodies), immunoglobulin classes G, M, and A, and CD19+ B-lymphocytes in patients with rheumatoid arthritis (RA) 12 and 24 weeks after initiation of therapy with a rituximab (RTM) biosimilar at a total dose of 1200 mg. Subjects and methods. Examinations were made in 20 patients with a reliable diagnosis of RA (including 18 women; median age, 61.5 [54; 66.5] years; disease duration, 39.5 [20; 84] years; DAS28, 5.6 [4.9; 6.8]). All the patients received two intravenous infusions of RTM (Acellbia®) 600 mg at a 2-week interval during therapy with methotrexate, nonsteroidal anti-inflammatory drugs, and glucocorticoids. Clinical and laboratory parameters were analyzed immediately before therapy and then 12 and 24 weeks after the first infusion of the drug. Results and discussion. DAS28, ESR, and CRP level in respondents significantly decreased 12 and 24 weeks after RTM administration. The serum IgM RF concentration in the respondents was found to be significantly reduced at weeks 12 and 24 and amounted to 79.7 and 87.1% of baseline, respectively. The IgA RF level significantly decreased by 72 and 85% of baseline at weeks 12 and 24 of RTM therapy, respectively, in patients with a good response, and by 59.7 and 67.5% at weeks 12 and 24 in patients with a satisfactory response. The serum concentration of anti-cyclic citrullinated peptide antibodies in the respondents remained high throughout the follow-up. All the patients achieved CD19+ B-cell depletion at week 12 of therapy (absolute levels, 0); there was an increase in the level of CD19+ B-lymphocytes at week 24 (0.0030 [0.0003; 0.0270] 109/l). In both in the good and satisfactory response groups, the mean immunoglobulin levels remained within normal limits. Conclusion. The analysis of the efficiency of two infusions of the RTM biosimilar at a total dose of 1200 mg following 24 weeks of therapy initiation suggests that the drug is able to cause reductions in disease activity, laboratory signs of inflammatory activity, autoantibody concentrations, and complete B-lymphocyte depletion.

© 2018 Ima-Press Publishing House.All right reserved. Impaired B-cell immunological tolerance plays a central role in the pathogenesis of autoimmune rheumatic diseases and autoimmune diseases of another nature. B-cells link innate and acquired immunity: they express Toll-like receptors that respond to danger signals; act as antigen-presenting cells; induce an antigen-specific immune response; determine the development of immunological memory; and synthesize a wide range of cytokines that regulate (stimulate or suppress) an immune response and inflammation. In autoimmune diseases, there are metabolic and B-cellular signaling disturbances that lead to defects in B-regulatory, T-regulatory, follicular T-helper, and dendritic cells. B-cells synthesize organ-nonspecific and organ-specific autoantibodies that are biomarkers for autoimmune diseases and play an important role in their immunopathogenesis. Anti-B-cell therapy that causes B-cell depletion in blood and target organs is effective in a wide range of autoimmune diseases. Its efficiency is determined by various mechanisms, such as suppression of pathogenic autoantibody synthesis; modulation of the function of B-cells (antigen presentation, cytokine synthesis, and costimulation), T-lymphocytes and dendritic cells. Further study of a strategy for targeted anti-B-cell therapy, mechanisms of action, and new targets is important for the progress of modern rheumatology to improve the treatment strategy of autoimmune rheumatic diseases.

© 2018 Ima-Press Publishing House. All right reserved. In accordance with international and Russian guidelines for the management of patients with rheumatoid arthritis (RA), after its diagnosis, a synthetic disease-modifying antirheumatic drug is prescribed, among these drugs, methotrexate is anchor and, when the latter is impossible to use, leflunomide is commonly administered. Objective: to evaluate the efficacy and safety of a leflunomide generic (Elafra) during a multicenter follow-up. Subjects and methods. The investigation enrolled 347 patients aged over 18 years who met the 2010 ACR/EULAR criteria for RA, had its duration of less and more than 2 years, signed informed consent, and followed up in 29 centers of Russia. Elafra was prescribed at a saturating dose of 100 mg for the first 3 days, then 20 mg/day. There might be a temporary two-fold reduction in the dose when adverse events (AE) occurred. The patients were examined before and 4, 12 and 24 weeks after beginning leflunomide treatment. The treatment efficiency was evaluated with DAS28 and CDAI and by the physician global assessment. Results and discussion. The patients were divided into two groups: 1) 125 patients with RA of less than 2 years' duration and 2) 222 patients with RA of more than 2 years' duration. The mean age of patients in Group 1 was 48.7±12.9 years; that in Group 2 was 52.5±11.95 years; the mean disease duration was 11.9±7.8 and 90.99±54.28 months, respectively. During 24-week treatment, there was a highly significant decrease in all assessed clinical, laboratory parameters and indices of RA activity in both groups. At 4 weeks of treatment, the effect was observed in 91.8% of the patients in Group 1 and in 84.6% in Group 2, whereas at 12 weeks the effect was noted in almost all patients (99.1% and 96.9% in Groups 1 and 2, respectively). The highest rate of AE during Elafra therapy was recorded in the early periods: at 4 weeks, AE were noted in 6.5% of the patients in Group 1 and in 9.9% in Group 2, without needing to discontinue the drug. Treatment continuation decreased the rate of AE. Because of its intolerance, Elafra was discontinued due to in one case in Group 1 (diarrhea at 24 weeks of treatment) and in 6 cases in Group 2 (at 12 and 24 weeks of treatment). Conclusion. Treatment with leflunomide (Elafra) leads to the rapid development of its effect in early and late RA in most patients and is characterized by a good tolerability.

© 2018 Ima-Press Publishing House. All rights reserved. Rheumatoid arthritis (RA) is an immunoinflammatory (autoimmune) rheumatic disease of unknown etiology, which is characterized by chronic erosive arthritis and systemic visceral organ damage that results in early disability and shorter patient survival. Despite RA treatment advances associated with the design of novel drugs and the improvement of treatment strategies to achieve remission in many patients, there are still many theoretical and clinical problems concerning both the definition of the concept of remission, its characteristics and types and approaches to the optimum policy of symptomatic and pathogenetic drug therapy at different stages of the disease, the use of which will be able to rapidly induce and maintain remission in the long-term. Further investigations are needed to study the nature of heterogeneity of pathogenetic mechanisms of RA and approaches to early diagnosis, to improve methods for monitoring disease activity and biomarkers for the efficiency of and resistance to therapy and, finally, to develop differentiation therapy, including those related to a search for new therapeutic targets.

© 2018 Ima-Press Publishing House. All rights reserved. Rheumatoid arthritis (RA) and the use of glucocorticoids (GCs) are proven risk factors for osteoporosis (OP) and osteoporotic fractures (OPF). There are also other reasons for increased fracture risk in RA. Objective: to determine the rate of RA in an epidemiological sample of persons aged 50 years and older and to identify those in need of antiosteoporotic therapy among the patients with RA in order to prevent OPF. Subjects and methods. The epidemiological sample included 18,018 people aged 50 years and older (13,941 women and 4,077 men; mean age, 62±10 years). The survey consisted of a unified questionnaire, measurement of daily dietary calcium intake, and calculation of a 10-year fracture risk using the FRAX® algorithm. Results and discussion. The prevalence of RA in the epidemiological population sample aged 50 years and older was 1.7% (1.9% in women and 1.2% in men; p=0.0047). The mean FRAX® values for major OPF in RA patients were significantly higher than those in non-RA individuals: 18.4±10 and 13.2±7.9%, respectively (p=0.0001) for women and 8.9±6.4 and 6.2±3.7%, respectively (p=0.0001) for men. 42% of the patients with RA were at high risk for OPF. Thus, 48% of the women with RA had FRAX® values above the therapeutic intervention threshold; and the non-RA group needed antiosteoporotic therapy significantly less (31%; p=0.00001). At the same time, the detection rate of high-risk OPF in men with and without RA did not differ significantly (8 and 5%, respectively; p>0.05). The most common risk factors (RFs) for OP and OPF in RA patients included previous fractures (33%), secondary causes of OP (30%), GC use (18%), and, additionally, smoking (33%) in male patients with RA. The female patients with RA significantly more frequently took GCs (17%) and had other secondary causes of OP and OPF (33%) than those without RA (7.7% (p=0.0001) and 23% (p=0.0004, respectively). The male patients with RA versus to the population-based control showed significant differences when they only used GCs (20 and 5%, respectively; p = 0.0001); the remaining RFs were encountered at the same frequency. Less than half of the normal daily calcium intake was observed in 20% of men and 16% of women (p=0.53). Conclusion. 42% of the RA patients aged 50 years and older were at high risk for OPF and needed antiosteoporotic therapy. Every third woman with RA had at least one other comorbidity or condition associated with the increased risk of OPF. In the male patients with RA, the FRAX® algorithm could reveal only 8% of persons at high risk for fractures, while 58% of them had two or more additional RFs that can negatively affect bone mineral density and increase the risk of fracture. To identify those who require prevention and treatment of OP and OPF, it is preferable to perform bone densitometry of the axial skeleton among male patients with RA.

© 2018 Media Sphera Publishing Group. All rights reserved. Research objective - comparative analysis of incidence and structure of anxiety-depressive spectrum disorders (ADD) in patients with various rheumatic diseases (RD). Materials and methods. 613 patients with RD were enrolled in the study: 180 with a reliable diagnosis of systemic lupus erythematosus (SLE), 128 with rheumatoid arthritis (RA), 110 with systemic sclerosis (SSc), 115 with Behcet's disease (BD), 80 with primary Sjögren's syndrome (pSS). Female prevailed in all groups (95% of patients with pSS, 88,2% - SSc, 87,2% - RA, 85,5% of SLE) except BD patients (70% male). The mean age was 42.3±1.54 years and was lower in patients with BD (33.3±0.98 years) and SLE (34.6±0.93 years) compared to patients with SSc (49.9±2.47 years), RA (47.4±0.99 years) and pSS (46.2±2.3 years). The mean RD duration was 130,0±8,65 months and was more at BD - 148,5±10,4 months, pSS - 141,6±8,92 months, RA - 138,4±10,1months, and less at SLE - 134,9±8,8 months and SSc - 87,0±5,04 months. The mean SLE activity index SLEDAI was 9,13±0,63 points (high), RA (DAS28) - 5,26±0,17 points (high), BD (BDCAF) - 3,79±0,2 points (moderate) and SSc by G. Valentini - 1,1±0,20 points (moderate). Glucocorticoids took 100% of patients with pSS, 91,1% - SLE, 90% - SSc, 87% - BD and 67,2% - RA patients; conventional disease modifying anti-rheumatic drugs (cDMARDs) took 90% of patients with SSc, 84% - BD, 79,6% - RA, 68% - pSS, 40,6% - SLE. Biologic DMARDs took 32% of patients with RA, 17,4% - BD, 7,3% - SSc and 7,2% - SLE. Mental disorders were diagnosed by psychiatrist as a result of screening by the hospital anxiety and depression scale (HADS) and in semi-structured interview in accordance with the ICD-10/ DSM-IV. The severity of depression was evaluated by Montgomery- Asberg Depression Rating Scale (MADRS) and anxiety - by Hamilton Anxiety Rating Scale (HAM-A). Projective psychological methods were used for cognitive impairment detection. Results. Screening of depressive disorders (HADS-D≥8) was positive in 180 (29,4%) patients with RD, including 74 (41%) patients with SLE, 38 (35%) - SSc, 29 (23%) - RA, 23 (20%) - BD and 16 (20%) - pSS; anxiety disorders (HADS-A≥8) - in 272 (44,4%) patients, including 66 (52%) patients with RA, 40 (50%) - pSS, 77 (43%) - SLE, 45 (41%) - SSc and 44 (38%) - BD. In accordance with the ICD-10/ DSMIV depressive disorders have been identified in 389 (63%) patients, including 94 (73%) patients with RA, 71 (64,5%) - SSc, 69 (60%) - BD, 90 (50%) - SLE and 39 (49%) - pSS; anxiety disorders - in 377 (61,5%) patients, including 20 (25%) patients with pSS, 44 (24,5%) - SLE, 29 (23%) - RA, 20 (17%) - BD and 7 (6,4%) - SSc. Conclusion. Anxiety-depressive spectrum disorders are typical for most patients with RA, SLE, SSc, pSS and BD. ADDs diagnosis in RD patients with the use of the HADS did not reveal a significant proportion. To obtain objective data on the frequency and structure of ADDs, psychopathological and clinical psychological diagnosis is necessary.

© 2018 Ima-Press Publishing House. Mental disorders (MDS) of the anxiety-depressive spectrum (ADS) and cognitive impairment (CI) substantially deteriorate the course and efficiency of therapy for rheumatoid arthritis (RA). There have been practically no studies on the impact of psychopharmacotherapy (PPT) for MDS on the efficacy of standard disease-modifying antirheumatic drugs (DMARDs) and biological agents (BAs). Objective: to investigate the impact of adequate PPT for MDS of ADS on the efficacy of DMARDs and BAs in patients with RA. Subjects and methods. The investigation included 128 patients (13% men and 87% women) with documented RA in accordance with the 1987 American College of Rheumatology (ACR) criteria. The patients' mean age was 47.4}0.9 years; the median duration of RA was 96 [48; 228] months. DAS28 averaged 5.34}0.17. 75.1% of the patients received DMARDs. The diagnosis of MDS was based on the ICD-10 codes, by applying a semi-structured interview and the Hospital Anxiety and Depression Scale. Changes in the pattern and severity of ADS were evaluated using the Hamilton Anxiety Scale and the Montgomery-Asberg Depression Rating Scale. Clinical and psychological procedures were used to diagnose CI. At baseline, ADS was detected in 123 (96.1%) patients: major depression in 41 (32.1%), minor depression in 53 (41.4%), and anxiety disorders in 29 (22.6%). CI was diagnosed in 88 (68.7%). PPT was offered to all the patients with MDS; 52 agreed to treatment and 71 refused. The following therapeutic groups were identified according to the performed therapy: 1) DMARDs (n = 39); 2) DMARDs + PPT (n = 43); 3) DMARDs + BAs (n = 32); 4) DMARDs + BAs + PPT (n = 9). The dynamics of MDS and the outcomes of RA were estimated in 112 (91.0%) and in 83 (67.5%) of the 123 patients at one-and five-year follow-ups, respectively. The efficiency of RA therapy was evaluated from the changes in DAS28 and SDAI. Results and discussion. One year later, the patients who had received the complete cycle of PPT and took DMARDs achieved a satisfactory effect twice more frequently (58.1 and 32.3%, respectively; relative risk (RR) = 0.53; 95% confidence interval (CI), 0.2-1.39; p = 0.024) and did not respond to therapy 3 times less often (21.0 and 58.1%, respectively; RR = 2.41; 95% CI, 0.87-6.71; p = 0.001) according to the EULAR criteria than those who had refused PPT. The patients with MDS who received DMARDs + PPT during one year were unresponsive to therapy significantly less frequently than those who received DMARDs and BAs without PPT (21 and 44.8%, respectively; RR = 0.6; 95% CI, 0.21-1.7; p = 0.029). After 5 years of follow-up, the probability of no response to RA therapy in MD patients who received only DMARDs was 3.6 times higher than in those who had PPT (66.7% and 10.4%, respectively; RR = 3.58; 95% CI 0.82-15.5; p < 0.001). The patients adequately treated with DMARDs and BAs for MDS according to the DAS28 showed 1.3-fold more frequently good and satisfactory results (100 and 76.2%, respectively; p = 0.14) than those who refused PPT, but these differences were not statistically significant because the DMARD+BA+PPT group was small. Five-year follow-up indicated that DAS28 remission was more common in the patients receiving DMARDs and PPT than in those who had DMARDs and no PPT (34.5 and 8.3%, respectively; RR = 1.79; 95% CI, 0.34-9.24; p = 0.024). DAS28 remission was somewhat more frequently observed among the patients receiving DMARDs, BAs, and PPT than among those taking DMARDs and BAs (33.3 19.0%, respectively; RR = 1.64; 95% CI, 0.28-9.57; p = 0.34), but these differences were insignificant. Remissions according to the 2011 ACR/EULAR criteria were achieved by only the patients having DMARDs and PPT (6.9% and 13.8% after 1 and 5 years, respectively). Conclusion. Adequate treatment of MDS in RA patients results in a significant increase in the efficiency of antirheumatic therapy.

© 2018 Ima-Press Publishing House. All right reserved. Objective: to analyze the levels of CD3+, CD3+CD4+, CD3+CD8+, and CD3-CD56+ T lymphocytes, FoxP3+ regulatory T cells (Treg), and CD19+ B lymphocytes in patients with early and advanced rheumatoid arthritis (RA). Subjects and methods. The investigation enrolled 45 patients previously untreated with methotrexate (MTX-naive) who had early RA and 15 patients who had advanced RA. Immunofluorescence staining and multicolor flow cytome-try assays were used to estimate the percentage and absolute (abs) counts of CD3+, CD3+CD4+, CD3+CD8+, CD3-CD16+CD56+, CD19+, Treg (FoxP3+CD25+; surface CD152+; intracellular CD152+; FoxP3+CD127; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; and FoxP3+CD274+. Results and discussion. The patients with early RA were found to have a lower percentage of FoxP3+CD25+ cells and lower percentages and abs counts of FoxP3+ ICOS+ cells, FoxP3+CD154+ cells, and FoxP3+ CD274+ T cells than healthy donors (p0.05 in all cases). The patients with advanced RA were also recorded to have a lower percentage of FoxP3+CD25+ cells and lower percentages and abs contents of FoxP3+ ICOS+ cells, FoxP3+CD154+ cells, and FoxP3+ CD274+ T cells (p0.05 in all cases). The patients with advanced RA compared to those with early RA had a higher content of CD4+ lymphocytes (50.7 [44.4; 53.1] and 45.0 [38.0; 49.2]) and lower percentages of CD25+CD127- T lymphocytes (5.0 [4.0; 5.7] and 6.5 [5.1; 7.9] respectively; p0.05 in all cases). Conclusion. Patients with RA (with the early or advanced stage of the disease) show a decrease in both the counts and functional activity of Treg. The patients with advanced RA compared with those with early RA showed an increase in CD4+ lymphocyte counts and a decrease in CD25+CD127- cell levels, which suggests that there are more pronounced impairments in Treg homeostasis in advanced RA.

© 2018 Ima-Press Publishing House. All right reserved. The response rate to therapy for rheumatoid arthritis (RA) rarely exceeds 60%. Mental disorders (MDs) of the anxiety-depressive spectrum (ADS) and cognitive impairment (CI) substantially affect the evaluation of the efficiency of RA therapy. Adequate psychopharmacotherapy is one of the possible approaches to optimizing the treatment of RA. The factors influencing the efficiency of RA therapy with standard disease-modifying antirheumatic drugs (DMARDs) and biological agents (BAs) in combination with adequate psychopharmacotherapy have not been previously identified. Objective: to determine the predictors of response to therapy in patients with RA receiving DMARDs and BAs with or without adequate psychopharmacotherapy for ADS disorders. Subjects and methods. The investigation included 128 patients (13% men and 87% women) with a reliable diagnosis of RA. At baseline, 75.1% of patients received DMARDs; 7.8% - BAs. ADS disorders were detected in 123 (96.1%) patients. Psychopharmacotherapy was offered to all the patients with MDs; 52 patients agreed to treatment and 71 refused. The following therapeutic groups were identified according to the performed therapy: 1) DMARDs (n = 39); 2) DMARDs + psychopharmacotherapy (n = 43); 3) DMARDs + BAs (n = 32); 4) DMARDs + BAs + psychopharmacotherapy (n = 9). The changes of MDs symptoms and the outcomes of RA were assessed in 83 (67.5%) patients at five-year follow-up. The efficiency of RA therapy was evaluated with DAS28 (EULAR criteria). Predictors of response to therapy were determined using linear regression modeling. Results and discussion. At 5 years, 22 (26.5%) and 37 (44.6%) patients were recorded to show good and moderate responses to therapy, respectively; 24 (28.9%) patients were non-respondents. The linear regression model included 14 factors (p<0.001). The high values of DAS28 (β=0.258) at the inclusion; belonging to therapeutic groups 2 (β=0.267), 3 (β=0.235), and 4 (β=0.210), the absence of diabetes mellitus (β=-0.230), and experience in using glucocorticoids (β=-0.230) were associated with a high likelihood of response to therapy; high body mass index (β=-0.200) and long RA duration (β=-0,181), a high level of rheumatoid factor (β=-0.176), a history of myocardial infarction (β=-0.153), schizotypic disorder (β=-0.132), and extra-articular manifestations of RA (β=-0.106), and older age (β=-0.102) were related to a low probability of response. The area under the ROC curve for the model was 0.99 (p<0.001). Conclusion. BA therapy and psychopharmacotherapy, along with younger age, shorter duration and high activity of RA, a low level of rheumatoid factor, lower body mass index, the absence of diabetes mellitus, myocardial infarction, and extra-articular manifestations of RA in the history, schizotypic disorder, and experience in using glucocorticoids are associated with a greater likelihood of a good and moderate treatment response.