The paper discusses the new mechanisms of osteoarthritis (OA) pathogenesis. Particular emphasis is placed on the role of subchondral bone remodeling, inflammatory mediators, bone morphogenetic proteins, etc. These data may be of great importance for elaborating new approaches to OA treatment.

The paper briefly presents some specific characteristics of development of a treat-to-target (T2T) strategy for spondy- loarthritis (SA). The reasons for some inconsistencies between the current concept of SA and the name of the paper presenting the program are described shortly. A complete Russian translation of the T2T strategy for this disease is given and major problems in its development are outlined. The main goal of therapy is shown to achieve clinical remission or low disease activity; however, there has not yet been a final definition of this condition. 

Objective: to estimate changes in cytokine profile versus disease activity in patients with early rheumatoid arthritis (RA) who use methotrexate (MTX) and adalimumab (ADA) in accordance with the treat-to-target concept. Subjects and methods. Forty-five patients (35 women; median age 53.5 [46; 59.5] years) with early RA (median dura- tion 7.0 [4.0; 11.5] months; DAS28 5.8 [4.9; 6.4]; rheumatoid factor positivity (RF+) 91%; anti-cyclic citrullinated peptide antibody positivity (ACCP) + 96%) were examined. In all the patients, MTX as the first agent was subcuta- neously used in a dose of 10 mg/week with its rapid escalation up to 20-25 mg/week. Serum cytokine concentrations were determined using the xMAP multiplexing technology before and 12 and 24 weeks after therapy.

Results. Following 12 weeks of therapy, DAS28 mean value decreased to 4.33 [3.5; 5.2] (p < 0.05 vs baseline). Twenty- nine (64.4%) patients responded to treatment. It was decided to continue MTX monotherapy in 23 patients (a monotherapy group) and in 22 patients ADA was added to therapy due to its inadequate effect in accordance with the standard regimen (a combined therapy group). At 24 weeks, mean DAS28 was 2.9 [2.1; 3.6] and 19 (82.6%) patients responded to treatment in the monotherapy group. In the combined therapy group, DAS28 was 3.4 [3.2; 4.4]; nearly 30% of the patients achieved remission/low disease activity and the number of patients with the high activity of a pathological process also declined significantly (from 59.1 to 13.6%).

At 12 weeks, the monotherapy group showed reduction of the level of proinflammatory (interleukin-6 (IL-6), IL-17, tumor necrosis factor-α (TNF-α)), anti-inflammatory (IL-4, IL-5, IL-9, IL-13) cytokines, chemokines (interferon induced protein-10 (IP-10)), and vascular endothelial growth factors (VEGF) (p<0.05); at 24 weeks, there were reductions in IL-6, IL-9, and IL-10, and transforming GF-bb and an increase in IL-10 concentration (p<0.05).

At 12 weeks of MTX therapy, the combined therapy group displayed a reduction in IL-6, IL-1Pa, IP-10 (p<0.05); at 24 weeks of treatment (12-week ADA administration) there were decreases in proinflammatory (IL-12), anti-inflammatory (IL-9) cytokines, chemokines (IP-10, monocyte chemoattractant protein, and macrophageal inflammatory protein-1β), VEGF and an elevation of IL-10. Conclusion. Thus, the results of the investigation suggest the high clinical efficiency of therapy with subcutaneous MTX, which is associated with the lower levels of a number of proinflammatory cytokines, chemokines, and growth factors. ADA treatment is also accompanied by decreased disease activity and positive changes in the cytokine profile, by exerting a higher impact on the level of chemokines and growth factors. 

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.

Rheumatoid arthritis (RA) is a proven high cardiovascular risk disease. High heart rate (HR), lower heart rate variabil- ity (HRV), and increased QT interval are considered as predictors of cardiovascular events in patients with coronary heart disease, chronic heart failure, and diabetes mellitus. In RA, there is a pronounced rise in HR, a reduction in HRV, and an increase in QT interval mainly due to the factors reflecting the severity of the disease. Rituximab (RTM) is successfully used to treat patients with high RA activity. At the same time there are only a few pieces of evidence for the effect of the drug on the cardiovascular system.

Objective: to study changes in HR, HRV, and QT interval values obtained during electrocardiography (ECG) Holter monitoring (ECG HM) in RTM-treated women during a 6-month follow-up.
Subjects and methods: The investigation enrolled 55 women (mean age 50 years) with a definite diagnosis of RA and its high activity. The patients were examined 6 months after administration of RTM. The latter was infused intra- venously twice (500 and 1000 mg in 22% and 78% of the patients, respectively) during therapy with disease-modifying antirheumatic and non-steroidal anti-inflammatory drugs and glucocorticoids. The RA patients were divided into two groups: 1) a satisfactory/good effect of RTM according to the EULAR criteria (n = 41); 2) no effect (n = 14). Analysis of 24-hour ECG HM yielded the values of HR and mean duration of corrected QT interval (QTc). The tim- ing HRV values obtained at ECG HM were standardized from age and mean HR (SDNNn, RMSSDn, and pNN50n).

Results. The baseline HRmin and HRmean values were higher and SDNNn was lower in the RA patients in Group 1 than those in Group 2 (p < 0.05). In Group 1, RTM therapy was accompanied by a reduction in HRmean and HRmin by 8% and by an increase in SDNNn by 3%, RMSSDn by 26%, and pNN50n by 33% whereas no significant changes in HR and HRV were found in Group 2. The RTM therapy-induced HRmean decrease was associated with the reductions of C-reactive protein concentration and HAQ disability index (p < 0.01), the increases of rMSSDn and pNN50n associated with lower HAQ index, ERS, and DAS28 (p < 0.01). There were no differences in QTc in Groups 1 and 2 during 6 months after RTM therapy. Thus, effective RTM therapy is attended by reduced HR and improved HRV values. 

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA).
Objective: to study the associations of the data of high-resolution computed tomography (HRCT) and the esti- mate of diffusing lung capacity (DLC) with clinical and laboratory parameters in RA patients with and without ILD.
Subjects and methods. 79 RA patients fulfilling the 1987 American College of Rheumatology criteria (61 women and 18 men) admitted to the Nasonova Research Institute of Rheumatology were included.
Results. HRCT revealed signs of ILD in 58 (73%) cases. The patients with ILD were divided into three groups: 1) 18 (31%) patients with ground glass opacities; 2) 34 (58.6%) patients with fibrosis; 3) 6 (10.4%) patients with the honeycomb lung. Twenty-one (27%) patients with ILD were included in Group 4. In the ILD patients with ground glass opacities, the levels of anti-cyclic citrullinated peptide (ACCP) antibodies and rheumatoid factor (RF) were much above those in the patients without ILD (240 [166; 410.5], 480 [140; 850.5] and 73 [31; 101], 330,5 [118.5; 604.8], respectively). In the patients with ILD, the concentration of C-reactive protein (CRP) (46 [35; 91]) was higher than that in those without ILD (24 [18; 31]; p < 0.05). In the ILD patients with ground glass opacities, DLC was considerably below that in those with ILD – 59.2±11.2 and 79.8±12.1% of the normal value, respectively (p < 0.001).
Conclusion. The associations found between ACCP antibodies and DLC, DAS28 and DLC may suggest that ACCP antibodies are implicated in the pathogenesis of ILD and the lung is involved in the immunoinflammatory process. The high percent of smokers detected in our investigation confirms the considerable role of smoking in the pathogene- sis of RA-associated ILD. In the RA patients with ILD, ground glass opacities must be an indicator of the activity of an immunopathological process in the lung.

The peak onset of rheumatoid arthritis (RA) is at 30-55 years of age. At this age, the patients have also other concomi- tant diseases (comorbidities) that affect the course and prognosis of RA, the choice of its treatment policy, quality of life of the patients.
Objective: to identify the most important and common comorbidities in patients with RA.

Subjects and methods. Two hundred patients (median age 55 [46; 61] years) were enrolled; there was a preponderance of women (82.5%) with median disease duration 5 [1; 10] years, seropositive for IgM rheumatoid factor (83.0%) and anti-cyclic citrullinated peptide antibodies (81.6%) with moderate and high disease activity (median DAS28 value 3.9 [3.1; 4.9]). Varying degrees of destructive changes in hand and foot joints were radiologically detected in 71.2% of the patients; 64.5% of the patients had Functional Class II. Methotrexate was given to 69.5% of the patients; therapy with biological agents was used in 21.0% of the cases. 15.5% of the patients did not receive DMARD or biologics. 43.0% of the patients with RA received glucocorticoids.

Results. Comorbidities were present in 72.0% of the patients with RA. The most common diseases were hypertension (60.0%), dyslipidemia (45.0%), fractures at various sites (29.5%), and coronary heart disease (21.0%). Myocardial infarction and stroke were observed in 1.5 and 1.0% of cases, respectively. There was diabetes mellitus (DM) in 7.5% of the cases and osteoporosis in 15.5% of the patients. 81.7% of the patients with RA and hypertension and 80.0% of those with RA and DM received antihypertensive and sugar-lowering therapy, respectively. At the same time the RA patients with dyslipidemia and osteoporosis received specific drugs far less frequently (30.0 and 29.0%, respectively). Conclusion. Comorbidities are frequently encountered in RA. By taking into account the fact that cardiovascular dis- eases are a main cause of death in RA; it is necessary to adequately and timely modify traditional risk factors (hyper- tension, dyslipidemia, and diabetes mellitus). Treatment patients with RA requires an interdisciplinary approach and an interaction between physicians of different specialties. 

Objective: To assess change of disease activity and the functional status of patients with ankylosing spondylitis (AS) during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), synthetic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor-α (TNF-α) inhibitors in a Bulgarian population.
Subjects and methods. Sixty-six patients with AS were examined at baseline and after 6 months 25 (37.9%) from them received NSAIDs, 14 (21.2%) – synthetic DMARDs (sulfasalazine and methotrexate), and 27 (40.9%) – TNF-α inhibitors (adalimumab and etanarcept). The disease activity was assessed by BASDAI, ASDAS-CRP, ASDAS-ESR, ESR, and C-reactive protein (CRP), as well as by physician's and patient's assessments. Functional failure was deter- mined by BASFI, DFI, HAQ-S, and BASMI. ASAS improvement criteria and ASDAS changes (clinical improvement Δ ≥1.1 units and considerable improvement Δ ≥2.0 units) were used to assess response to therapy. ASAS criteria were employed to confirm remission.

Results. After 12 months of NSAID therapy, there was a statistically significant decrease of CRP level (p < 0.05) and an increase of DFI (p < 0.05). ASAS and ASDAS-ESR 20% improvement Δ ≥1.1 was noted in one case; ASAS 5/6 in 8% of cases. There was a 40% improvement and partial remission in ASAS, as well as in ASDAS Δ ≥2.0 in none patient. Treatment with synthetic DMARDs showed no statistically significant changes in activity and functional sta- tus and ASAS 20% response in 14.3% of the patients. A 40% response in ASAS, ASAS5/6, ASDAS Δ ≥1.1 and ASDAS-ERS Δ ≥2.0 was seen in 7.1%. No partial remission was observed. TNF-α inhibitor treatment provided sig- nificant improvement of all activity and function indicators (Δ ≤ 0.001). There was ASAS 20% response in 63% of cases, 40% response in 48.1%, ASAS5/6 in 59.3%, partial remission in 33.3%, ASDAS-CRP Δ ≥1.1 in 66.7%, ASDAS-CRP 2.0 in 48.1%, ASDAS-ESR Δ≥1.1 in 63% and ASDAS-ESR Δ≥2.0 in 37% of cases. Comparison of therapy response showed that the use of TNF-α inhibitors provided better results (p <0.001).
Conclusion. TNF-α inhibitors are the most effective agent to suppress disease activity and to improve functional status in AS. 

Objective: to elucidate the role of peripheral arthritis in ankylosing spondylitis (AS) and its impact on therapy choice in daily practice of rheumatologists.
Subjects and methods. The investigation enrolled 330 consecutive patients with AS referred to rheumatologists during 4 months in 24 cities and towns of the Russian Federation. A specially designed clinical schedule was filled out for all the patients.

Results. Peripheral arthritis was present in 47% of patients, including in 17 and 46% who had upper and lower limb joint involvement, respectively. Patients with peripheral arthritis had higher ESR, BASDAI and ASDAS-ESR levels. They were also found to have more marked functional disorders than the patients with its isolated axial variant. The clinical signs of hip joint involvement were detected in 56% of the patients and they were bilateral in 43%. In the rheumatologists' opinion, 24 (8%) needed total hip joint replacement.

Conclusion. Peripheral arthritis aggravates AS.

Objective: to assess quality of life of male gouty patients with SF-36 questionnaire versus the standardized indicators of population-based control.
Subjects and methods. The study included 153 male patients with gout, in each case the diagnosis was verified by detection of monosodium urate crystals. The patients' mean age was 47.5±12.9 years (25 to 74 years); the median dis- ease duration was 5.6 [3.03; 9.7] years. The SF-36v1 questionnaire was used to compare the quality of life of the patients with the standardized indicators of the Russian population. The comparison was made separately in different age groups: 25–34 years (n=23), 35–44 years (n=48), 45–54 years (n=44), 55–64 years (n=20), 65–74 years (n=18). Results. In the gouty patients, the physical health component summary score was lower (39.8±9.1; p < 0.00001) and the mental health component summary score (51.72±8.3) did not differ from that in the population. The greatest dif- ferences were revealed in 4 scales reflecting the physical health component. The gouty patients versus the controls were found to have significantly higher scores of physical functioning (46.1±10.03 and 51.75±9.71; p < 0.0001), role physical functioning (46.7±9.9 and 51.56±9.92; p < 0.0001), pain intensity (45.41±10.11 and 51.64±10.20; p < 0.0001), and general health condition (47.73±9.6 and 51.47±10.15; p < 0.0001, respectively). Of statistical signifi- cance were also differences in the scales of vital capacity (p = 0.0006) and social functioning (p = 0.020). In the male gouty patients, the mental health and role emotional functioning scores were similar to the population-based control ones. Comparative analysis revealed the above-mentioned similar differences in different age groups.

Conclusion. The physical health of the gouty patients is mainly poor and their mental health is poor to a lesser degree; their social adaptation is decreased.

Anterior uveitis is the most common form of intraocular inflammation. Among them, HLA-B27-associated uveitis occupies one of the leading places, which may be an independent disease or one of the manifestations of spondy- loarthritis (SA). The paper considers the general issues of the nomenclature and classification of uveitis, by using the classification criteria of the International Uveitis Study Group and the Standardization of Uveitis Nomenclature Workshop. The epidemiological aspects of uveitis are described. Emphasis is laid on a difference in the detection rate of uveitis in different countries, in men and women, as well as in different forms of SA. The clinical features of SA- associated uveitis and its complications are discussed. 

The whole armory of the drugs used in rheumatology is employed to treat systemic lupus erythematosus (SLE); how- ever, most of them have not got regulatory authorities' approval and are used off-label for SLE. The successful use of a biological agent rituximab (anti-CD20 monoclonal antibodies) and the registration of belimumab (anti-BLyS mono- clonal antibodies) for the treatment of SLE have spurred the development of novel approaches to treating this disease. 

The past decades are marked by the obvious progress in rheumatology, which is related to the practical introduction of biological agents. At the same time the use of these drugs is associated with the increasing risk of infections of different nature and locations, including opportunistic ones (invasive mycoses, Pneumocystis pneumonia, etc.), and with the greater risk of reactivation of latent infection, primary with that of tuberculosis. Beyond that point, there are cases of severe infections (pneumonia, sepsis, bacterial arthritis, skin and soft tissue lesions, etc.), including those with a fatal outcome. This review analyzes mainly the past 3-year literature data on the rate and location of infections treated with biologics, which have been obtained in the placebo-controlled and direct comparative studies of patients with rheuma- toid arthritis. It characterizes the importance of different infections (tuberculosis, pneumonia, chronic viral hepati- tides, herpesvirus infections, etc.) for treatment policy in the above patients. This underlines the need for wider immu- nization with different vaccines (chiefly against pneumococcus and influenza) in patients with autoimmune inflam- matory rheumatic diseases. 

The paper reviews data on the incidence of rheumatoid arthritis, disability, and the cost of treatment, including thera- py with biological agents.

Objective: to estimate the frequency of use of antiosteoporotic drugs in daily clinical practice and treatment adherence in patients.
Subjects and methods. Questionnaires were used to interview two patient groups: 1) 198 women with osteoporosis (OP) with duration ≥3 years; 2) 186 women over 50 years of age who had sustained low-trauma fractures (LTF) at different sites and undergone assessments of therapy prescription and adherence 12 and 18 months after fracture.

Results. In Group 1 patients with OP, 16, 24, and 38% of the women took antiosteoporotic treatment for >3, 2-3, and 6 months to 1 year, respectively; and 22% did not start pathogenetic therapy. Treatment adherence was significantly higher among those who were followed at the specialized OP Center. In Group 2, 56% of the patients had received therapy following LTF and 44% had not, which was due to the absence of primary care physicians' recommendations in half of the cases. 24% were treated after LTF within the first year and only 19% of the women were at 18 months. Treatment was recommended by the specialists of the OP Center in 89% of the cases and by primary care physicians in 11%. Within a year, repeated fracture occurred in 9% of the patients; among them none received pathogenetic treat- ment. A questionnaire survey of the patients indicated that they preferred to use drugs more rarely rather than every day. At the same time no advantages of any one route of drug administration were found.

Conclusion. There is a low frequency of using pathogenetic treatment in patients with OP, particularly in those who are followed up in the district outpatient departments, which is due to both the absence of physicians' prescription of antiosteoporotic drugs and inadequate treatment adherence in patients. Both patient motivation to long-term treat- ment and OP education programs among primary care physicians are needed to improve the quality of medical care to osteoporotic patients. 

Objective: to evaluate the efficacy, tolerance, and safety of Carmolis topical gel in patients with gonarthrosis.
Subjects and methods. The investigation enrolled 60 patients with knee osteoarthrosis (OA) who were divided into two groups: 1) 40 patients received Carmolis topical gel in addition to nonsteroidal anti-inflammatory drugs (NSAIDs); 2) 20 patients took NSAIDS only (a control group). The treatment duration was 2 weeks. In both groups, therapeutic effectiveness was evaluated from changes in the WOMAC index, pain intensity at rest and during movement by the visual analog scale (VAS). The disease activity was also assessed by a physician and a patient (a Likert scale), local swelling and hyperthermia of the affected joint, the efficiency of treatment, and daily needs for NSAIDs were deter- mined.
Results. The performed treatment in both patent groups showed positive clinical changes. Combination therapy involving Carmolis gel displayed greater reductions in WOMAC pain and resting and movement pain than in the con- trol group (as assessed by VAS). On completion of the investigation, considerable improvement was, in the physicians' opinion, noted in 38 (95%) patients using Carmolis, which coincided with self-evaluations of the patients. During Carmolis application, the starting dose of NSAIDs could be reduced in 18 (45%) patients. Adverse reactions occurred infrequently and required no therapy discontinuation.
Conclusion. Carmolis topical gel is effective in relieving clinical symptoms in patients with gonarthrosis, well tolerated, and safe, which can recommend its use in the combination treatment of knee OA.

The EULAR-2013 Congress took place in Madrid on 12–15 June 2013. The problem of spondyloarthritis (SA) was one of the significant aspects at this scientific forum. It should be primarily pointed out that the congress presented a T2T (treat-to-target) initiative to treat this disease. According to this concept, the main goal of SA therapy, as that for rheumatoid arthritis, is remission or low activity although there is no clear definition of these conditions in SA. A con- siderable amount of time was devoted to the results of recent SA pathogenesis investigations, including the role of interleukin 23. Discussions around the proposed SA classification concerning the criteria for mainly axial and periph- eral SAs and their clinical variety did not cease either. Reports on already well-known and novel treatment options and their efficiency during long term follow up held a prominent position at the congress. 

Starting working meeting on «Russian Register of Patients with ANCA-Associated Systemic Vasculitis» (28 April, 2014, Moscow)