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On 30 May, 2024, an expert meeting was held to update the approaches for the treatment of axial spondyloarthritis (axSpA). A new approach to the treatment of axSpA was considered, which consists of depleting autoreactive TRBV9+ T- lymphocytes by introducing a monoclonal antibody – the drug seniprutug. The value of the drug seniprutug in the treatment of the disease was discussed and key aspects for the incorporation of the drug seniprutug into real-world clinical rheumatological practice were agreed.

Relevance. Pneumococci are among the most common causative agents of severe bacterial infections in humans. The prevalence of invasive pneumococcal infections among people with autoimmune inflammatory rheumatic diseases is 3–4 times higher than in the general population. Aim. To evaluate the effectiveness of vaccination with 13-valent pneumococcal conjugate vaccine (PCV 13) in patients with rheumatoid arthritis (RA). Materials and Methods. The data of scientific publications PubMed, Web of Science, elibrary, the National Inpatient Database of the USA, the Moscow Unified Register of Arthritis, the V. A. Nasonova Research Institute of Rheumatology were used in the review. V. A. Nasonova Research Institute of Rheumatology. Conclusion. In the presented review in adult patients with rheumatoid arthritis (RA) receiving various antirheumatic drugs, the immunogenicity (humoral response, opsonophagocytic activity), safety of vaccines of 13-valent conjugated pneumococcal vaccine (PCV13) was assessed. Based on the data presented, a conclusion was made about the safe management of PCV13 and the formation of antibodies to pneumococcus in RA patients with targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), biologic (bDMARDs) and Glucocorticoids (GCs < 15 mg daily). Methotrexate (MTX) in RA patients reduced the pneumococcal response and the functional activity of antibodies.

Rituximab is a chimeric (mouse and human) monoclonal antibody against B-lymphocytes (CD20). This drug is widely used in rheumatology in the treatment of rheumatoid arthritis, Sjogren’s syndrome, some systemic connective tissue diseases and vasculitis, as well as in hematology in lymphoproliferative diseases. Administration of rituximab leads to depletion of B-lymphocytes through various mechanisms, including antibody-dependent and complementdependent cytotoxic effects, as well as the regulation of apoptosis. Considering the mechanism of autoimmune damage in Graves’ disease, an autoimmune thyroid disease accompanied by thyrotoxicosis and endocrine ophthalmopathy (an autoimmune lesion of the accessory apparatus of the eye), the use of rituximab may be effective in these diseases. The review considers the currently available results of studies on the use of various doses of rituximab in these diseases.

Currently, a large number of highly effective biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are used for the treatment of rheumatoid arthritis (RA). However, in addition to effectiveness, it is necessary to evaluate the risk of adverse events (AEs) when using them.Objective: to determine the predictors of bDMARDs and tsDMARDs discontinuation due to AEs in patients with RA.Patients and methods. The study included 661 patients with RA who took bDMARDs and tsDMARDs. The search for predictors of targeted therapy discontinuation due to AEs was carried out in two stages. At the first stage, using the Kaplan-Meier method, we selected indicators that showed the greatest significant single-factor relationship with the duration of retention on therapy. At the second stage, significant independent indicators were obtained by iterative selection of variables within the multivariate proportional risk model according to Cox.Results and discussion. The presence of rheumatoid nodules (p

Inflammatory bowel disease IBD (Crohns disease CD, ulcerative colitis UC) immune-mediated diseases of the digestive tract of unknown etiology. The basis of the pathogenesis of IBD is a violation of the protective mechanisms of the intestinal barrier as a result of a complex interaction of environmental factors, a genetic predisposition and defects in the activation of the immune response in the lymphoid tissue of the intestinal mucosa. Three groups of antibodies are detected in the sera of IBD patients: autoantibodies, antimicrobial antibodies and antibodies to peptide antigens. In CD, the most useful diagnostic markers are ASCA; in UC patients pANCA. Antibodies are not among the diagnostic criteria for CD and UC, the diagnosis of which is traditionally made on the basis of a complex of clinical, radiological, endoscopic and histological signs, but can be used as useful additional non-invasive markers for early diagnosis, assessment of clinical phenotypes, prognosis and effectiveness of treatment of these diseases.

Aim. Analysis of survival on biological therapy in previously bionaive patients with rheumatoid arthritis (RA) during the first year of therapy in real clinical practice. Materials and methods. The retrospective study included 204 adult patients with RA. In the hospital, patients were first prescribed therapy with various biological disease-modifying antirheumatic drugs (bDMARDs): infliximab, adalimumab, etanercept, certolizumab pegol, tocilizumab, abatacept (ABA), rituximab (RTM). Patients were divided by age in accordance with the classification adopted by WHO. Clinical forms of RA were presented: RA, seropositive for rheumatoid factor, RA, seronegative for rheumatoid factor, RA with extra-articular manifestations, adult-oneset Stills disease, juvenile RA. The reasons for the cancellation of bDMARD during the first year of treatment were: insufficient effectiveness (including primary inefficiency), adverse events, administrative reasons, clinical and laboratory remission, death. Results. A year after being included in the study, treatment was continued in 92 (45%) patients and was discontinued in 112 patients. The average time of treatment amounted to 0.750.33 years. The longest duration of treatment was in the RTM and ABA groups (0.920.22 and 0.830.29 years, respectively). In 56 (50%) patients, bDMARD was canceled due to insufficient effectiveness (including primary inefficiency), 28 patients (25%) due to the development of adverse reactions, 19 (17%) patients for administrative reasons, 7 (6.25%) patients due to drug remission. During the first year of therapy, there were 2 (1.75%) deaths due to severe comorbid conditions in patients, one of whom received RTM, the other tocilizumab. Conclusion. Study showed that 45% of patients with RA continue treatment with first-time bDMARD for more than 12 months. The most common reason for discontinuation of therapy was its lack of effectiveness. The best survival rate of bDMARDs was observed in RTM and ABA. When selecting bDMARD in each case, it is necessary to take into account the continuity at all stages of treatment.

Objective: to analyze the results of tofacitinib (TOFA) therapy in real clinical practice according to the All-Russian Arthritis Registry (OREL). Subjects and methods. The OREL Registry included 347 patients (286 (82%) women and 61 (18%) men) with rheumatoid arthritis (RA) who initiated TOFA therapy. The male:female ratio was 1:4.7. The patients’ median age at onset of the disease was 42 years; its duration was 8 years. Most of the patients included in the registry had extended- (n=171 (52%)) or late- (n=148 (45%)) stage of RA. Results and discussion. Prior to initiation of TOFA therapy, RA activity according to DAS28 was high and moderate in 91 (64.5%) and 40 (28.4%) patients, respectively; the median DAS28 value was 5.5 [4.6; 6.2]; SDAI – 30.5 [21.4; 42.9], and CDAI – 28.2 [20.0; 37.1]. The use of TOFA was accompanied by significant decrease of disease activity. After 12 weeks, high RA activity was persistent in 32 (22.7%) patients; the number of patients with moderate activity increased to 77 (54.6%), that of those with low activity rose to 15 (10.6%); remission was observed in 17 (12.1%) patients. 216 (62.6%) and 76 (22%) patients received TOFA as first- and second-line therapy, respectively. TOFA was most frequently prescribed when tumor necrosis factor-á inhibitors (19.6%), rituximab (7.8%), tocilizumab (4.3%), and abatacept (5.2%) were insufficiently effective or poorly tolerated. Conclusion. The results of using TOFA in real clinical practice may suggest that the drug has high efficacy in patients with RA. TOFA can be used at a dose of 5 or 10 mg twice daily as both alone and in combination with disease-modifying anti-rheumatic drugs. TOFA showed similar efficacy in patients who had earlier taken biological agents and in those who had not.

Janus kinase (JK) inhibitors block the intracellular signaling pathways that are responsible for the synthesis of proinflammatory cytokines and mediators, which in turn cause the activation of pain receptors and central sensitization (CS). It is suggested that JK inhibitors can rapidly eliminate pain and reduce the severity of CS.Objective: to evaluate the effect of the JK inhibitor tofacitinib (TOFA) on the intensity of pain and the signs of CS in patients with active rheumatoid arthritis (RA) at 7 and 28 days after therapy initiation.Patients and methods. A study group consisted of 39 patients (79.5% female) (mean age 50.9±11.1 years) with RA (DAS28 5.8±0.6). Of these, 89.7% were seropositive for rheumatoid factor; 82.0% took methotrexate and 18.0% received leflunomide. All the patients were prescribed TOFA 5 mg twice daily due to the inefficacy or intolerance of biological agents. The investigators estimated pain intensity using a Brief Pain Inventory (BPI), rated the presence of a neuropathic pain component (NPC) with the PainDETECT questionnaire, and assessed the signs of CS with the Central Sensitization Inventory (CSI) during the first 4 weeks after TOFA administration.Results and discussion. The patients initially experienced moderate or severe pain (the mean scores of 5.33±2.51 on the numerical rating scale (NRS) included in BPI); 53.8% had signs of CS (CSI scores of ≥40); 17.9% had signs of a NPC (PainDETECT scores of >18). Already on day 7 after the start of TOFA administration, there was a statistically significant decrease in the mean NRS pain intensity scores to 4.06±2.2 (p=0.01) and by 29.4±17.9%, as shown by the patient's assessment of the analgesic effect of therapy (BPI), as well as the severity of CS, namely a decrease in the mean NRS pain score to 35.9±11.2 (p=0.01). On 28 days, the effect became better: there was a reduction in the level of NRS pain to 2.32±1.57 (p

A wide range of biological agents recently introduced into clinical rheumatology determines a special interest in their tolerance. The paper presents the authors’ own data, as well as a review of foreign literature on this issue.Objective: to analyze the tolerability of infliximab (INF) in patients with rheumatoid arthritis (RA) in real clinical practiceSubjects and methods. The analysis included 135 RA patients receiving INF alone or in combination with diseasemodifying antirheumatic drugs.Results and discussion. The total tolerance of INF was satisfactory. Adverse reactions (ARs) were noted in 28.1% of cases, including in 19 (14.1%) patients who had serious ARs that required drug discontinuation.Conclusion. The best tolerance was observed with a combination of INF and methotrexate. The authors draw attention to the need for medical examination prior to each drug administration.

Aim: To evaluate the effectiveness, safety and anti-destructive effect of anti-B-cell therapy (rituximab) in various combinations (RTM-mono, RTM + DMARD, RTM + GK) in patients with rheumatoid arthritis in real clinical practice.Materials and methods: Clinical and radiological evaluation of 110 patients with rheumatoid arthritis who received rituximab therapy (RTM) as monotherapy (group 1), in combination with methotrexate (group 2), leflunomide (group 3), and group 4 with other basic anti-inflammatory drugs.Results: When assessing at 48 weeks of treatment with these regimens, the achievement of remission and a low degree of activity was observed in 22.36% of patients. An X-ray evaluation showed the absence of progression in the total score in 60.9%. When assessing progression in the monotherapy group, there was no progression in 76.92%, in the group of PTM + MT – in 54.29%, in the group of PTM + LEF – 65.0%, in the group of other DMARDs – 50% of patients. When assessing the clinical effect in the group receiving GK – remission and a low degree of activity – 19.67% of patients, in the group without GK – 21.05%. Assessing the radiological dynamics, it was shown that in the group not receiving GK – inhibition by the total score occurred in 54.55%, receiving – 61.54%.Conclusion: This work has demonstrated the high therapeutic efficacy of RTM in real clinical practice. There were no significant differences in the degree of progression depending on the concomitant therapy of DMARDs or GK. In the treatment of RTM, inhibition of articular destruction is possible even against the background of clinical deterioration.

Background: An important characteristic of immune pathology in rheumatoid arthritis (RA) is a B-cell tolerance defect, associated with autoantibodies production, and antigen-specific activation of Th-1 CD4+ T lymphocytes with an excess production of pro-inflammatory cytokines compared to anti-inflammatory ones. Pro-inflammatory cytokines contribute to the development of local inflammatory effects, induce bone destruction and pannus formation, and contribute to the development of autoimmune abnormalities and systemic manifestations. Anti-inflammatory cytokines are able to reduce the rate of joint destruction. There is evidence of the involvement of Th2 cytokines in the development of early RA. These facts suggest the need for a thorough investigation into the balance between the Th1 and Th2 types of immune response at different stages of the disease.Aim: To assess the importance of сytokine profiling in the evaluation of immune abnormalities in RA.Materials and methods: In this descriptive, controlled, retrospective study, we examined 118 patients with RA and 33 healthy donors as a control group. Serum IgM rheumatoid factor (RF) and C-reactive protein (CRP) levels were measured by immunonephelometry; anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) were determined by an enzyme immunoassay, cytokines levels with "xMAP" technique.Results: Serum cytokine levels vary depending on RA duration. The cytokine profile in early RA, unlike that in established RA with a duration of more than 6 months, is characterized by higher levels of pro-inflammatory (MIP-1α), Th1 (IFN-γ), and Th17 (IL-17) cytokines, colony-stimulating factors (IL-7, G-CSF), and chemokines (IL-8, IP-10) (p < 0.05 for all parameters). In established RA, the levels of pro-inflammatory (IL-1β, -6, -15, TNF-α), anti-inflammatory (IL-1ra, IL-10, IL-13, IL-5), Th1 (IL-2, IL-12), Th2 (IL-9) cytokines and colony-stimulating factors (G-CSF, GM-CSF) correlate with the concentrations of IgM RF and antibodies to citrullinated proteins (antiCCP, anti-MCV) (all p < 0.05). There was also а correlation between CRP and pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IL-12), Th2 (IL-5, IL-9) cytokine levels and between DAS28 and pro-inflammatory cytokine (IL-6) and colony-stimulating factor (G-CSF) levels (all p < 0.05). Conclusion: In RA, cytokines, chemokines and colony-stimulating factors mirror the inflammatory activity of the disease. Changes in blood concentrations of cytokines enable to get an insight into the complex interplay of numerous mediators of innate and acquired immunity.

Objective: to study the efficacy, immunogenicity, and safety of a 23-valent pneumococcal polysaccharide vaccine (PPSV-23) in patients with rheumatoid arthritis (RA) receiving disease-modifying antirheumatic drugs (DMARDs) and biologic agents (BAs) during a 5-year follow-up.Patients and methods. The investigation included 79 RA patients with a recent history of ≥2 episodes of lower respiratory tract infections (bronchitis, pneumonia). A single dose (0.5 ml) of PPSV-23 was administered subcutaneously during continued methotrexate/leflunomide therapy or 28–30 days before using TNF-α inhibitors. All the patients were followed up during the first year; 39 patients at 24 months (Visit 5), 13 at 36 months (Visit 6), 23 at 48 months (Visit 7), and 18 at 60 months (Visit 8).Results and discussion. RA patients receiving various therapies were noted to have a marked positive immune response to PPSV-23, which was manifested by a significant increase in the postimmunization response coefficient. Vaccination responses were recorded in 61% of the patients with RA. The level of postvaccination responses tended to decrease at the 4-year follow-up. Only one case of community-acquired pneumonia of unknown etiology was detected at 5 years of follow-up.Conclusion. The data obtained by the authors for the first time in the 5-year prospective study indicate the sufficient and long-term immunogenicity, high efficacy, and safety of PPSV-23 in RA patients treated with DMARDs and BAs. Further clinical trials are needed to clarify the influence of various factors on the efficacy and immunogenicity of PPSV-23 and on the degree of their correlation in patients with RA.Objective: to study the efficacy, immunogenicity, and safety of a 23-valent pneumococcal polysaccharide vaccine (PPSV-23) in patients with rheumatoid arthritis (RA) receiving disease-modifying antirheumatic drugs (DMARDs) and biologic agents (BAs) during a 5-year follow-up.Patients and methods. The investigation included 79 RA patients with a recent history of ≥2 episodes of lower respiratory tract infections (bronchitis, pneumonia). A single dose (0.5 ml) of PPSV-23 was administered subcutaneously during continued methotrexate/leflunomide therapy or 28–30 days before using TNF-α inhibitors. All the patients were followed up during the first year; 39 patients at 24 months (Visit 5), 13 at 36 months (Visit 6), 23 at 48 months (Visit 7), and 18 at 60 months (Visit 8).Results and discussion. RA patients receiving various therapies were noted to have a marked positive immune response to PPSV-23, which was manifested by a significant increase in the postimmunization response coefficient. Vaccination responses were recorded in 61% of the patients with RA. The level of postvaccination responses tended to decrease at the 4-year follow-up. Only one case of community-acquired pneumonia of unknown etiology was detected at 5 years of follow-up.Conclusion. The data obtained by the authors for the first time in the 5-year prospective study indicate the sufficient and long-term immunogenicity, high efficacy, and safety of PPSV-23 in RA patients treated with DMARDs and BAs. Further clinical trials are needed to clarify the influence of various factors on the efficacy and immunogenicity of PPSV-23 and on the degree of their correlation in patients with RA.

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.

Objective: to evaluate the safety and effectiveness of vaccination with trivalent split virion influenza vaccine in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), estimate the effect of vaccination on rheumatoid disorder (RD) activity and influenza and influenzalike illnesses morbidity.Materials and methods. The study included 86 patients (58 females and 28 males aged 22–82 years) with RDs (52 patients with RA and 34 patients with AS), as well as 40 subjects without RD (control group). At the time of study inclusion, all patients were receiving drug therapy. Duration of RD varied from 2 months to 46 years. The Vaxigrip vaccine containing the currents trains of the flu virus for 2016–2017 season or 2017–2018 season was administered subcutaneously as 1 dose (0.5 ml) with continuing antirheumatic therapy. The main control stages were visits 1, 3, and 6 months after vaccination. During the visits, standard clinical and labtests, clinical examination with disease activity evaluation were performed.Results. In 98 patients, vaccination tolerability was high, no post vaccination reactions were observed. In 20 cases, pain, swelling, and hyperemia of the skin 2 cm in diameter at the point of vaccination were observed; in 8 cases, low-grade fever, myalgia, discomfort, headache were observed. No RD flares or development of new autoimmune disorders were diagnosed during the follow-up period. No cases of influenza or influenza-like illnesses were registered during the follow-up period.Conclusion. The obtained data demonstrate high tolerability, clinical effectiveness of trivalent split virion influenza vaccine in patients with RA and AS.

The aim of the study was to study the efficacy, safety and immunogenicity of trivalent split influenza vaccine in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic scleroderma (SSD). Material and methods. Ninety three patients were enrolled in the study, including 52 patients with RA, 34 with AS, 7 with SSD, and also 40 persons without rheumatic diseases (RD) (control group). At the time of enrolment, all patients received RD drug therapy. The duration of RD was from 2 months up to 46 years. Vaxigrip vaccine, which included the actual strains of influenza virus for the 2016-2017 or 2017-2018 seasons was administered subcutaneously in the amount of 1 dose (0.5 ml) against the backdrop of continuing RD therapy. The main stages of control were visits at 1-, 3- and 6-month intervals after vaccination. Standard clinical and laboratory tests, a clinical examination of the patient and assessment of disease activity were performed during the visits. Immunogenicity of the vaccine was evaluated at each stage of the control procedure using the commercial ELISA kits manufactured by PPDP LLC (St. Petersburg). Results. No cases of influenza or influenza-like illness were recorded during the entire period of observation. 81% of patients had no post-vaccination reactions in the RD group. Pain, swelling and hyperaemia of the skin with a diameter of up to 2 cm at the injection site were reported in 14% of cases and subfebrility, myalgia, malaise, headache in 5% of cases. The frequency of postvaccinal reactions among patients was not significantly different from that in the control group. There were no cases of exacerbation of RD or the occurrence of any new autoimmune disorders. The parameters of the humoral immune response in patients with RD did not significantly differ from those in the control group. Conclusion. The obtained data testify about good clinical efficacy and tolerability of trivalent split influenza vaccine in patients with RD.

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

Objective: to estimate changes in the cytokine profile in patients receiving abatacept (ABC).Subjects and methods. The investigation enrolled 44 patients with rheumatoid arthritis (RA) who had been unsuccessfully treated with disease-modifying antirheumatic drugs and biological agents. A control group included 16 healthy donors. The majority of patients were women who were positive for rheumatoid factor (RF) (80%) and antibodies to cyclic citrullinated peptide (ACCP) (79.5%); the mean age was 49.6±13.9 years; the median disease duration was 2 [1.4; 3] years with high RA activity (mean DAS28, 5.2±0.8). The serum concentrations of interleukin (IL) 1β, IL-6, IL-17AF, tumor necrosis factor-α (TNF-α), VEGF-A, IP-10, and YKL-40 were measured by enzyme immunoassay before and 6 months after ABC therapy. Disease activity was assessed using DAS28 every 3 months. ABC was infused intravenously according to the standard regimen.Results and discussion. The patients with RA as compared with the control group had significantly elevated levels of IL-6 (2.4 [1.1; 6.4] and 0.7 [0.62; 1.0] pg/ml; p=0.0002), YKL-40 (97 [68.4; 97.9] and 64 [52.4; 107.5] pg/ml; p=0.03), IP-10 (21 [12.9; 49.8] and 14 [9.2; 15.2] pg/ml, respectively; p=0.005). ABC caused a significant decrease in RA activity after 3 months of therapy (p

Tofacitinib (TOFA), a representative of a new class of targeted synthetic disease-modifying antirheumatic drugs (s-DMARD), is a promising drug for treating rheumatoid arthritis (RA) and other immune inflammatory diseases.Objective: to evaluate the efficiency and safety of therapy with TOFA in combination with methotrexate (MTX) and other s-DMARDs in real clinical practice in patients with active RA and previous ineffective therapy.Patients and methods. A 6-month Russian multicenter study of function and quality of life enrolled 101 patients with resistant RA: 18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months; rheumatoid factor-positive individuals (89.1%); and anticyclic citrullinated peptide antibody-positive ones (74.7%). 93 (92,1%) of these patients completed a 24-week study. TOFA was used as both second-line drug (after failure of therapy with s-DMARD) (n=74) and as a third-line drug (after failure of therapy with s-DMARDs and biological agents (BAs) (n=74). The tools RAPID3, HAQ, and EQ-5D were used to determine disease outcomes from a patient's assessment.Results. All the three tools demonstrated significant positive changes at 3–6 months following therapy initiation. RAPID3 scores for the status of a patient achieving a low disease activity or remission coincided with the mean DAS28-ESR and SDAI scores in 60% and 68% of cases, respectively. The achievement rates of the minimally clinically significant improvement (ΔHAQ≥0.22) and functional remission (HAQ≤0.5) at 6 months of TOFA therapy were 79.6 and 30.1%, respectively. The mean change value in EQ-5D scores over 6 months was -0.162±0.21. There were no significant between the groups of patients who used TOFA as a second- or third-line agent in the majority of indicators, except EQ-5D scores at 6 months.Conclusions. The results of our multicenter study using considerable Russian material confirmed the pronounced positive effect of TOFA used as a second-line agent (after s-DMARD failure) and a third-line agent (after s-DMARD and BA failure) on patients' assessment of disease activity, functional ability in daily life, and quality of life.

Objective: to compare the efficacy and safety of abatacept (ABC) in patients with different duration of rheumatoid arthritis (RA).Subjects and methods. The investigation enrolled 86 patients with previous inefficiency or intolerability of therapy with synthetic disease-modifying antirheumatic drugs (DMARDs), mainly with methotrexate, and/or biological agents (BAs), such as adalimumab, etanercept, rituximab, infliximab, certolizumab pegol, and tocilizumab. The patients were divided into 2 groups. Group 1 included 29 (34%) patients with early RA (< 2 years' disease duration); Group 2 consisted of 57 (66%) patients with long-term RA (> 2 years' disease duration). The patients' mean age was 49±13.4 years; most of them were women who had a high RA activity (the mean DAS28 value was 5.2±1.15), were seropositive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. All the patients underwent standard clinical and laboratory examinations. ABC was injected intravenously at a dose of 10 mg/kg according to the standard regimen. Every 3 months, disease activity was assessed with DAS28; functional status was evaluated with the Health Assessment Questionnaire (HAQ).Results and discussion. In the early and advanced RA patients, the mean DAS28 at baseline was 5.2±0.9 and 5.2±1.3, respectively. After 3 months of ABC treatment, it significantly decreased in both groups (p < 0.05). An improvement according to the criteria of the European League Against Rheumatism (EULAR) occurred in 76% of the early RA patients and in 74.5% of the advanced RA ones. Following 3 and 6 months of therapy, there were no significant differences between the two groups in the rate of a good response: the latter was obtained in 31 and 42% of early RA cases and in 25.5 and 40% of advanced RA cases, respectively. After 3 and 6 months, both groups showed a comparable number of those who did not respond to treatment (24 and 12.5% in the early RA group and 25.5 and 25% in the advanced RA group, respectively). During ABC therapy, both groups also displayed a significant decrease of HAQ disability index (DI) (p < 0.05). A total of 14 adverse events (AE) were recorded in 13 (15%) patients. The most common AE proved to be acute respiratory viral infections that were observed in 6 (7%) patients. Serious AE were seen in 3 (3.4%) patients. Conclusion. ABC therapy leads to decrease of RA activity in the majority of patients who have previously received ineffective therapy with DMARDs and BAs. There were no significant differences in good response rates according to the EULAR criteria between the advanced and early RA groups. Following 3 months of treatment, the decrease of HAQ DI was significantly more pronounced in the early RA group. AE were registered only in 15% of the patients. ABC has established itself as an effective drug that has a good safety profile and is able to occupy a niche in the therapy of both late and early RA.

Russian and international clinical recommendations postulate the possibility of withdrawal of biological agents in patients with rheumatoid arthritis (RA) after the achievement of clinical remission. But it is not clear what would be the results of implementation of these recommendations in clinical practice.Patients and methods. In REMARCA (Russian invEstigation of MethotrexAte and biologicals for eaRly aCtive Arthritis) trial 78 patients (66 females, 12 males, median age 53 years, duration of disease 7 months at inclusion), who were resistant to high doses of subcutaneous (SC) methotrexate (MTX), were treated by combination therapy with SC MT and biologics (adalimumab, certolizumab or abatacept). Patients were investigated every 3 months using DAS28-ESR, SDAI, CDAI indices as disease activity measures.Results. 30 (38.5%) patients (from 78) continued combination therapy. In 47 (60.3%) after achievement of remission or low disease activity (LDA) the therapy was modified to one of two options: 1) in 21 (26.9%) patients doses of biologics were tapered, in some cases to zero; 2) in 26 (33.3%) patients single-step discontinuation of biologics was performed. After 6 months among 47 patients with modification of therapy 27 (57.4%) maintained remission or LDA, in 20 (42.6%) deterioration observed, including 6 (12.8%) patients who lost remission but remained in LDA, and 14 (29.8%) flared (activity increased to moderate or high levels). First modification option was significantly superior to second option regarding the maintaining remission or LDA.Conclusion. In terms of maximum preservation of the results, optimal modification of treatment strategy is the tapering of the dose by the gradual increase in the period between injections of biologics, at least 12 months after reaching the state LDA or clinical remission.

The paper presents the materials of the Russian Arthritis Registry (OREL) that includes 3276 patients from 11 Russian Federation's largest research-and-practical centers situated in Moscow, Saint Petersburg, Novosibirsk, Kazan, Tula, Yaroslavl, Tyumen. It discusses the main goals of setting up registries, compares the results of an analysis of the data available in the Russian Registry OREL and registries of European countries and the USA. The findings suggest that there is non-uniform information on clinical, laboratory, and instrumental parameters in the national registers of a number of European countries and the USA. According to its basic characteristics, the Russian Registry OREL compares favorably with a number of other registries in the completeness of data collection, which allows a general idea of rheumatoidarthritis (RA) patients in Russia. For further development of the OREL Registry, it is necessary to concentrate our attention on the following main areas: to improve the quality of filling out documents; to follow-up patients receiving different RA therapy regimens according to the guidelines of the Association of Rheumatologists of Russia for the treatment of RA; to conduct in-depth studies of comorbidity, primarily depressive disorders; to analyze adverse reactions that make RA therapy difficult; to actively use modules for patients' self-rating of their condition; to develop nursing care, etc.

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilitiesof its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care.Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis.Subjects and methods. The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide anti body positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficientlyeffective, it was substituted for a BA from another class.Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued ubcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6- and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was45.7% and 28.3%, respectively (p=0.047).Conclusion. The treat-to-target strategy should be used in real clinical practiceand can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherapy.

Authors report new recommendations of All-Russian Public Organization «Association of Rheumatologists of Russia» (ARR) on treatment of rheumatoid arthritis (RA), which adapts contemporary concept accepted in the respective field of pharmacotherapy known as «Treat to Target». According to it, the main objective of RA pharmacotherapyis a remission (or low disease activity). To achieve it, disease modifying anti-rheumatic drugs (DMARD) should be administered to all RA patients as early as possible, with efficacy monitoring and therapy correction according to the disease activity. Special attention has been paid to the use of methotrexate (MTX) as «the gold standard» of RA pharmacotherapy and the key component of «Treat to Target» strategy. Early MTX administration (including subcutaneous injections) should become an obligatory component of RA treatment at all stages of the disease. If MTX is not efficient or not well tolerated (including subcutaneous form of the drug) as monotherapy or combined with conventional DMARD, biological agents should be used. Those include TNFα inhibitors, antagonist of interleukin-6 receptor (Tocilizumab), anti-B-cell drugs Rituximab) and agents blocking T-cell activation (Abatacept). Tofacitinib therapy (JAK inhibitor) is indicated in patients who are resistant to conventional DMARDs and biologics. All biologics and Tofacitinib are more effective in combination with MTX (or other DMARD).

Tofacitinib (TOFA), a member of a new class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), is a promising medication for the treatment of rheumatoid arthritis (RA) and other immunoinflammatory diseases. The paper describes the Russian experi-ence with TOFA used to treat severe RA.Patients and methods. 101 RA patients (18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months) who were positive for rheumatoid factor (89.1%) and anti-cyclic citrullinated peptide antibodies (74.7%) and resistant to therapy with synthetic DMARDs (sDMARDs) (80.2%) and biological agents (19.8%) were given TOFA at a dose of 5 mg twice daily, which could be doubled if necessary. TOFA was used alone (n=9) or in combination with methotrexate (MT) (n=75) or other sDMARDs (n=17). The achievement of low disease activity (LDA) and clinical remission at 3 and 6 months of treatment by DAS28-ESR SDAI, and CDAI scores, and the indices of safety and tolerability were assessed.Results. A total of 93 (92.1%) of the 101 patients completed a 24-week period of the investigation. 8 (7.9%) patients prematurely discontinued TOFA after an average of 2.75±0.71 months. At the end of the study, the patients achieved the primary endpoint (LDA including remission) in terms of DAS28-ESR ≤3.2 (34.7%), SDAI ≤11 (47.5%), and CDAI ≤10 (48.5%) and the secondary endpoints (clinical remission) in terms of DAS28-ESR ≤2.6 (17.8%), SDAI ≤3.3 (8.9%), and CDAI ≤2.8 (6.9%). When TOFA was combined with MT, the discontinuation rate for the former was significantly lower (2.7%) than when TOFA was used in combination with other sDMARDs (29.4%) or alone (11.1%; p

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.

The early administration of methotrexate (MTX) and the use of its high (by the rheumatology practice standards) doses contribute to the enhanced efficiency of therapy and the reduced severity of rheumatoid arthritis (RA). One of the important merits of MTX in the treatment of RA is the possibility of adjusting its dose and choosing its (oral or subcutaneous) administration routes, which makes it possible to individualize treatment. Particular emphasis has been recently placed just on a subcutaneous MTX formulation that creates prerequisites for substantially improving the efficiency of RA therapy. The paper gives the data of the REMARCA (Russian investigation of methotrexate and biologicals for early active arthritis) trial assessing the results of RA treatment in the use of the subcutaneous MTX dosage form as a first-line drug and in the elaboration of management tactics for this disease.Subjects and methods. The investigation included 191 patients (34 men and 157 women) with active RA; of whom 51.8% had very early RA (< 6 months' disease duration). 115 patients with RA completed a 24-month follow-up period; and their data were analyzed in more detail.Results and discussion. The findings may substantiate treatment policy based on the prescription of subcutaneous MTX (without previously administering its oral formulation) in patients with early RA and high disease activity, starting the drug at 15 mg/week and rapidly escalating with the highest tolerable doses during 4-8 weeks, which allows remission (or low disease activity) in the majority of patients without using glucocorticoids and biological agents.

Objective. To assess efficacy and tolerability of infliximab in pts with rheumatoid arthritis (RA) in real clinical practice.Materials and methods. 75 RA pts with high disease activity according to DAS 28 in 80% who received previous antirheumatic drugs without proper effect were included in an open clinical trial. DAS 28 and ACR criteria were used as primary outcome measures.Results. Infliximab administration provided significant clinical improvement in most pts. Already in a week after the first infusion 20% ACR improvement was achieved in 74% of pts. Significant improvement of all the main treatment effect parameters was achieved after the second infusion. ESR and CRP mean values normalized after the third infusion. Rheumatoid factor decrease was noted after 6 weeks. Mean values of tender and swollen joint counts significantly decreased but arthritis signs remained in a part of pts. Clinical remission was achieved in 4 (19%) from 21 pts completed a year’s course of treatment and in 4 pts the treatment was not effective. Serious adverse events requiring infliximab withdrawal (including infectious arthritis, hand phlegmon and bronchitis) appeared in 7 ptsConclusion. These results show high efficacy of infliximab and prove advisability of its administration in RA

Objective: to investigate the distribution of the genotypes and alleles of the PTPN22, TNFAIP3, CTLA4, TNFA, IL6, IL6R, IL10, MCP1, and ICAM1 genes in patients with rheumatoid arthritis (RA) and in the control group of healthy individuals, to estimate their significance as molecular genetic markers for predisposition to RA; and to analyze the correlation between the gene polymorphisms included in the study and the production of anti-cyclic citrullinated peptide antibodies (ACCPA) and IgM rheumatoid factor (RF).Subjects and methods. The investigation was conducted within the framework of the «Early arthritis: Diagnosis, outcome, criteria, active treatment program». The prospective follow-up study included 122 patients with RA fulfilling the 1987 American College of Rheumatology (ACR) criteria; with disease duration of ≤ 2 years. 73 (59.8%) patients were included during the first 6 months after the onset of the disease. 74 (60.7%) and 81 (66.5%) patients were found to be positive for ACCPA and IgM RF, respectively. 314 healthy blood donors served as a control group. A real-time polymerase chain reaction was used in the patients and control individuals to study the distribution of the polymorphic variants of PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs6920220, rs10499194), CTLA4 (+49A>G, rs231775 ), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -1082 A>G, rs1800896), MCP1/CCL2 (+2518A>G, rs1024611), and ICAM1 (721G>A, rs1799969) genes. Results and discussion. This analysis revealed an association of PTPN22 (+1858 C >T, rs2476601) and TNFAIP3 (rs675520, rs10499194) polymorphisms with the risk of RA (odds ratio (OR), 1.5; 95% confidence interval (CI), 1.0–2.3; p = 0.05; OR, 1.5; 95% CI, 1.1–2.0; p = 0.02; OR, 0.5; 95% CI, 0.4–0.8; p = 0.01, respectively. Further, there was a tendency towards a positive association of TNFAIP3 (rs6920220) and IL6R (rs8192284) polymorphisms with a predisposition to RA (p = 0.056). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not associated with the risk of RA. An analysis of the findings after patient stratification by ACCPA and IgM RF (a binary variable) showed that none of the polymorphisms in question was associated with RF state. At the same time, PTPN22 (rs2476601), TNFAIP3 (rs675520), TNFAIP3 (rs10499194), and TNFА (rs1800629) polymorphisms were found to be significantly related to ACCPA state (a binary variable). The level of ACCPA as a quantitative variable was statistically significantly associated with CTLA4 (rs231775) and TNFА (rs1800629) polymorphisms in a dose-dependent fashion (р = 0.025 and р = 0.015, respectively). There was a marked tendency towards an association of ACCPA levels and IL6R gene polymorphism (p = 0.07). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not correlated with ACCPA state (binary and quantitative variables).Conclusion. The findings suggest that a number of genes are implicated in the pathogenesis of RA and that they are involved in the development of ACCPA-positive and ACCPA-negative RA subtypes. No relationship was found between the production of IgM RF and the polymorphisms of the genes under study. The findings suggest that there appears to be different mechanisms for the formation of autoantibodies (ACCPA and IgM RF) in RA.

Analysis of the literature on anti-cytokine therapy demonstrates the effectiveness of this therapy, compared with conventional glucocorticosteroid and immunosuppressive therapy. Drugs with anti-cytokine mechanism of action can be used in Ophthalmology, as inhibitors of angiogenesis in neovascularization and anti-inflammatory therapy in uveitis. Route of administration of TNF inhibitors are intravenous and subcutaneous. They can be used as monotherapy or with the glucocorticosteroid and immunosuppressive therapy. From the literature it is obvious, that the effect of the use of this group of drugs are dose-dependent and they can be positive (anti-angiogenic and anti-inflammatory) and negative – toxic. In a comparative aspects, studies show, that Infliximab has more pronounced anti-inflammatory effect, but at the same time, use of Infliximab is more often with side effects and complications. According to different authors, doses that cause side effects, are not comparable. It seems that, localization of inflammatory process plays a role in the vascular tract of the eye (front, rear), etiologic factor, causing the inflammation and, of course, the intensity of cytokine responses. Therefore, the question, the efficacy and tolerability of anti-cytokine drugs are dose-dependent, and whether, there are other factors that influence on the success of treatment -remains open. To answer these questions is required a detailed study, investigating the influence of this group of drugs on the eye tissues, pathological angiogenesis processes depending on the drug, the dose and the conditions of its application, and testing of optimal dosage of drugs to avoid side effects

Tofacitinib (TOFA) was the first synthetic small molecule drug which was comparable with genetically engineered biological agents (GIBA) in terms of its therapeutic effect in rheumatoid arthritis (RA). Results of treatment of over 4 thousand RA patients showed that the most common adverse events were nasopharyngitis, upper respiratory infections and urinary tract infections, herpes, diarrhea, nausea, gastritis. Serious side effects were registered in 15.4% of patients, and serious infections in 4.5%. Opportunistic infections occurred in 0.6% of patients, half of which were cases of tuberculosis. Anemia, hemocytopenia, increased lipidemia, a mild temporary decrease in glomerular filtration rate and increased creatinemia were also recorded. There were no anaphylactic or other immediate reactions. TOFA administration results were not different from those after treatment with GIBA in terms of mortality, incidence of infections and cancer.

The paper presents the materials of the Russian Arthritis Registry (OREL) that includes 3276 patients from 11 Russian Federation's largest research-and-practical centers situated in Moscow, Saint Petersburg, Novosibirsk, Kazan, Tula, Yaroslavl, Tyumen. It discusses the main goals of setting up registries, compares the results of an analysis of the data available in the Russian Registry OREL and registries of European countries and the USA. The findings suggest that there is non-uniform information on clinical, laboratory, and instrumental parameters in the national registers of a numberof European countries and the USA. According to its basic characteristics, the Russian Registry OREL compares favorably with a number of other registries in the completeness of data collection, which allows a general idea of rheumatoid arthritis (RA) patients in Russia. For further development of the OREL Registry, it is necessary to concentrate our attention on the following main areas: to improve the quality of filling out documents; to follow-up patients receiving different RA therapy regimens according to the guidelines of the Association of Rheumatologists of Russia for the treatment of RA; to conduct in-depth studies of comorbidity, primarily depressive disorders; to analyze adverse reactions that make RA therapy difficult; to actively use modules for patients' self-rating of their condition; to develop nursing care, etc.

Objective: to analyze the relationship of the clinical and antidestructive effect of infliximab (INF) to its total dose in patients with rheumatoid arthritis (RA).Subjects and methods. A one-year investigation included 135 patients with RA. All patients received INF 3 mg/kg at weeks 0, 2, 4 and then every 8 weeks. During each visit, the number of tender and swollen joints, C-reactive protein level, and erythrocyte sedimentation rate were determined and the Health Assessment Questionnaire (HAQ) was filled out. DAS-28 changes were used to assess therapeutic effect of INF. Joint destruction was evaluated by the Sharp method modified by van der Heijde. All patients were examined according to the protocol before each INF infusion. The result of INF therapy was assessed at week 54 in all patients (including in those who had not completed a one-year INF therapy cycle). According to the total dose of INF, the patients were divided into three groups: 1) ≤4 infusions (low-dose, n = 63); 2) 5–7 infusions (medium-dose, n = 31); 3) ≥8 infusions (full-dose, n = 41). Group 1 received an average of 2.5 IFN infusions; Group 2 and 3 – 5.8 and 8.8 infusions, respectively.Results. Baseline high disease activity (DAS28 > 5.1) was noted in the majority of the patients: 69% in Group 1, 86.6% in Group 2, and 62.1% in Group 3. All the patients showed a prompt (just at 14 weeks of treatment) and significant (p < 0.05) decrease of RA activity. This reduction remained significant at week 54. By the end of follow-up there were more patients with low disease activity (including those with DAS28 remission) in Group 3 than the other groups (53.9% versus 27.3 and 50% in Groups 1 and 2, respectively). After the completion of therapy, the highest percentage of patients with high disease activity was seen in Group 1 (36.4%). The number of remissions was comparable in Groups 2 and 3 (28.6 and 23.1%, respectively) and smaller in Group 1 (18.2%). Significantly more obvious radiographic disease progression was noted in Group 1 than in the two other groups.Conclusion. The lower total dose of INF can cause a long-lasting clinical effect in some patients with RA, but it does not substantially suppress joint destruction. There were no significant differences between patients receiving medium and full doses of this drug in and the degree of radiographic disease progression.

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilities of its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care. Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis. Subjects and methods. The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide antibody positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficiently effective, it was substituted for a BA from another class. Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued subcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was 45.7% and 28.3%, respectively (p=0.047). Conclusion. The treat-to-target strategy should be used in real clinical practice and can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherapy.

Authors report new recommendations of All-Russian Public Organization «Association of Rheumatologists of Russia» (ARR) on treatment of rheumatoid arthritis (RA), which adapts contemporary concept accepted in the respective field of pharmacotherapy known as «Treat to Target». According to it, the main objective of RA pharmacotherapy is a remission (or low disease activity). To achieve it, disease modifying anti-rheumatic drugs (DMARD) should be administered to all RA patients as early as possible, with efficacy monitoring and therapy correction according to the disease activity. Special attention has been paid to the use of methotrexate (MTX) as «the gold standard» of RA pharmacotherapy and the key component of «Treat to Target» strategy. Early MTX administration (including subcutaneous injections) should become an obligatory component of RA treatment at all stages of the disease. If MTX is not efficient or not well tolerated (including subcutaneous form of the drug) as monotherapy or combined with conventional DMARD, biological agents should be used. Those include TNFα inhibitors, antagonist of interleukin-6 receptor (Tocilizumab), anti-B-cell drugs (Rituximab) and agents blocking T-cell activation (Abatacept). Tofacitinib therapy (JAK inhibitor) is indicated in patients who are resistant to conventional DMARDs and biologics. All biologics and Tofacitinib are more effective in combination with MTX (or other DMARD).

Objective: to compare the efficiency and safety of four treatment regimens using methotrexate (MT), leflunomide (LEF), and a combination of MT and glucocorticoids (GC) for early rheumatoid arthritis (RA) (disease duration

The review analyzes trials dealing with the safety of golimumab (GLM) used in rheumatology. This drug was the latest Contact: Galina Lukina;gvl3@yandex.ru Поступила 12.05.14tumor necrosis factor α (TNF-α) inhibitor introduced into clinical practice and therefore the estimation of its tolerability is particularly relevant. The data obtained in large-scale clinical trials suggest that GLM has a good safety profile. The most common adverse events (AE) were infections, more often mild. The rate of infections was higher with the use of GLM 100 mg than with that of 50 mg. The overall cancer rate did not increase during a follow-up of less than 160 weeks. However, the rate of lymphomas in patients receiving GLM 100 mg proved to be higher than in those taking GLM 50 mg, in the general population, and in the placebo group in particular. AE were evenly distributed among patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Overall, the findings are in agreement with the data on the safety of previously used TNF-α inhibitors. No fundamentally new AE have been encountered. It is necessary to accumulate data on the use of GLM in real clinical practice, which will be able to more objectively define its place in the current therapy of rheumatic diseases.

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilities of its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care.Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis.Subjects and methods.The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide antibody positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficiently effective, it was substituted for a BA from another class.Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued subcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6- and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was 45.7% and 28.3%, respectively (p=0.047).Conclusion. The treat-to-target strategy should be used in real clinical practice and can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherapy

Authors report new recommendations of All-Russian Public Organization «Association of Rheumatologists of Russia» (ARR) on treatment of rheumatoid arthritis (RA), which adapts contemporary concept accepted in the respective field of pharmacotherapy known as «Treat to Target». According to it, the main objective of RA pharmacotherapy is a remission (or low disease activity). To achieve it, disease modifying anti-rheumatic drugs (DMARD) should be administered to all RA patients as early as possible, with efficacy monitoring and therapy correction according to the disease activity. Special attention has been paid to the use of methotrexate (MTX) as«the gold standard» of RA pharmacotherapy and the key component of «Treat to Target» strategy. Early MTX administration (including subcutaneous injections) should become an obligatory component of RA treatment at all stages of the disease. If MTX is not efficient or not well tolerated (including subcutaneous form of the drug) as monotherapy or combined with conventional DMARD, biological agents should be used. Those include TNFα inhibitors, antagonist of interleukin-6 receptor (Tocilizumab), anti-B-cell drugs (Rituximab) and agents blocking T-cell activation (Abatacept). Tofacitinib therapy (JAK inhibitor) is indicated in patients who are resistant to conventional DMARDs and biologics. All biologics and Tofacitinib are more effective in combination with MTX (or other DMARD).

Objective: to determine the predictors of the efficiency of rituximab (RTM) therapy through analysis of blood gene expressions in patients with rheumatoid arthritis (RA). Subjects and methods. Sixteen patients (mean age 53.4±10.8 years) with RA (mean duration 8.2±7.1 years) who had previ- ously received disease-modifying antirheumatic drugs and tumor necrosis factor-α (TNF-α) inhibitors without effects were examined. Each patient underwent a treatment cycle with RTM in a dose of 0.5-1 g. A control group included 26 healthy individuals. Clinical response was assessed with DAS28. Erythrocyte sedimentation rate (ESR), serum levels of anti-cyclic citrullinated peptide antibodies, C-reactive protein (CRP), and rheumatoid factor (RF) were estimated. Bone erosions and joint space narrowing were evaluated radiologically. RNA was isolated from blood and used to estimate the expression of the mTOR, ULK1, caspase 3, p21, TNF-α, cathepsin K, matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), inter- feron-γ (IFN-γ), and cyclooxygenase-2 (COX-2) genes by real-time reverse transcriptase polymerase chain reaction. Results. At the beginning of the investigation, the expression of all the genes under study was increased (p < 0.05) in the patients with RA versus the healthy individuals. RTM therapy resulted in reductions in DAS28, ESR, CRP levels, and CD10+ B lymphocyte depletion (p < 0.05). There were no changes in the number of erosions and the width of the joint space during RTM therapy. The blood expression of the mTOR, p21, caspase 3, ULK1, TNF-α, IL-1β, and cathepsin K genes was suppressed to that of healthy individuals. As compared to the beginning of the investigation, the expression of MMP-9 was also reduced (p < 0.05); however, it remained far higher than that in the controls and no drastic changes occurred in the expression of the IFN-р and COX-2 genes. Conclusion. Blood gene expression analysis may serve as a source of information on the status of patients with RA dur- ing RTM therapy. The higher residual expression of MMP-9, IFN-γ, and COX-2 may be a reason for the preserved activity of RA and its exacerbation.

Along with its basic activity in removing B-lymphocytes, rituximab (RTM) causes depletion of a population of CD20+ T cells that can pro- duce a variety of immunoregulatory and proinflammatory cytokines and chemokines. Objective: to define a role of multiplex cytokine analysis in the evaluation of the efficiency of using RMT in rheumatoid arthritis (RA). Subjects and methods. Thirty-four patients with the valid diagnosis of RA according to the ACR criteria of 1987 were examined. The con- centrations of cytokines were measured using the xMAP technology (27-plex). Results and discussion. In the group of patients with a clinical response to therapy with the gene engineering biological agent, there was a decrease in the concentrations of interleukins (IL) 1β, 1ra, 2, 4, 6, 9, and 13, granulocyte macrophage colony-stimulating factor (GM- CSF), γ-interferon (IFN-γ), monocyte chemoattractant 1 at week 8 of therapy; that in IL 1β, 1ra, 2, 5, 6, 9, 10, 12, 13, and 15, fibroblast growth factor 2 (FGF-2), GM-CSF, IFN-γ, and tumor necrosis factor-α at week 24, and that in IL-9 at week 40. The no-clinical response group showed a reduction in GM-CSF at week 8 and in IL-2 and macrophage inflammatory protein 1β (MIP-1β) at week 40, and an increase in IL-8 at week 8. At week 8 after drug infusion, the elevated levels of IL-17 and MIP-1β can be identified as possible early pre- dictors of a response (at week 40). Comparison of the baseline cytokine levels in the groups with different clinical response demonstrated a more than three-fold increase in the concentrations of IL 4, 5, 7, 8, 10, 12, 13, 15, 17, IFN-γ, and vascular endothelial growth factor, and IL-8 at weeks 8 and 40, respectively.

Objective. To study efficacy and safety of different schemes of alflutop (AT) administration in pts with osteoarthritis (OA). Material and methods 45 pts (40 womene and 5 men) with knee or hip OA or nodular form of the disease were included. Mean age was 60,3± 10,0 years, mean disease duration - 8,0±6,0 years, mean duration of the last exacerbation - 5,6±5,4 months. Pts with 2 (27 pts) and 3(15 pts) X-ray OA stage and 2 functional class (30 pts) prevailed. Pts were devided into 3 comparable groups, 15 pts in each. Pts of the group 1 received AT I ml/day intramuscularly (im) during 3 weeks, group 2 pts received intra-articular (ia) injections of AT 2 ml twice a week for 3 weeks and then im for 20 days. In group 3 ia (6) and im (20) injections were performed^simultaneously. During 12 months of follow up every pt received 2 appropriate courses. Results. 41 pts completed the study. AT significantly decreased joint pain at rest and at movement measured visual analog scale and WOMAC index in all groups. It also improved functional activity of pts (according to WOMAC index). Improvement according to doctor assessment was achieved after the second course in 78% of pts in group I, in 92% in group 2 and in 86% in group 3. Sonography of knee joints showed significant decrease of synovial membrane thickness (as a sign of synovitis) as well as increase parts of intra-articular hyaline cartilage thickness in group 2 and 3 pts. There was no radiological progression year of follow up. Tolerability was good. The drug was stopped due to adverse events in only 3 pts (dermatitis at the site of injection-1, increase of joint pain after intra-articular injections- 2) . In 3 other pts side effects were mild, and treatmend was continued. Conclusion. Combined Im and AT administration provides anti-inflammatory, analgesic and possible chondroprotective effect in OA pts.

Objectives: This article reports 1-year clinical outcomes of patients with rheumatoid arthritis (RA) receiving abatacept (ABA) therapy. Materials and methods: Patients (n=91) with high RA activity (DAS28 = 5.1 ± 1.0) and an inadequate response on synthetic DMARDs (mainly methotrexate, 70.3%) and biologics (mainly TNF-α inhibitors, 93%) were included in the study. The majority of patients were middle-aged (49 ± 13.5) womens, RF (72.5%) and ACPA (77%) positive, with moderate functional impairment - HAQ = 1.4 (0.9-2). ABA were administered IV, 10 mg/kg according to the standard scheme. The evaluation of the effectiveness of the therapy was carried out according to the EULAR / ACR 2011 criteria using SDAI, CDAI, HAQ and the intention to treat approach. Results: ABA led to a significant (p

The paper summarizes the data of international and Russian studies concerning current approaches to the pharmacotherapy of rheumatoid arthritis. Particular emphasis is placed on the substantiation of the treat-to-target concept, on the efficacy and safety of genetically engineered biological agents, including the inhibitors of tumor necrosis factor, interleukin-6 receptors, T-lymphocyte co-stimulation, and anti-B-cell therapy.