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-1 β (IL-1 β ), 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-1 β , 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.

Autoimmune (immunoinflammatory) rheumatic diseases are defined as clinical syndromes whose development is associated with the abnormal activation of T cells, B cells, and many other cells of the immune system, which gives rise to the progressive inflammation and destruction of the viscera. In spite of the high efficiency of combined therapy with biologic agents and standard disease-modifying antirheumatic drugs, primarily methotrexate, less than half of patients with rheumatoid arthritis (RA) could achieve a significant clinical effect and, very rarely, sustained remission. The combined influence of genetic and environmental factors may lead to loss of immunological tolerance, the basis for which is an imbalance between the effector and regulatory components of the immune system. To restore tolerance without chronic nonspecific immunosuppression observed in the use of majority of current anti-inflammatory drugs (including GEBAs) is regarded as the most important task of pharmacotherapy for RA. The aim of the review is to discuss firstly the role of the so-called T regulatory (Treg) cells as one of the critical components for the maintenance of tolerance and secondly promises for the pharmacotherapy of RA associated with the correction of the functional activity of Treg cells.

Matrix metalloproteinases (MMPs) are a group of over 20 proteolytic enzymes responsible for cleavage of protein components of the extracellular matrix. Three types of MMPs play an important role in the development of joint damage in patients with rheumatoid arthritis (RA): collagenases (MMP1, 8 and 13), stromelysins (MMP3), and gelatinases (MMP9). MMP3 is considered to be one of the key mediators of joint damage. Increased serum level of MMP is not specific for RA and may be registered in other rheumatic diseases (osteoarthritis, psoriatic arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus); however, monitoring of the level of MMP is of particular clinical importance in patients with RA. MMP3 serum level may be a useful marker of disease activity. Several studies have shown a correlation of MMP3 concentration with clinical and laboratorial parameters of inflammatory activity (ESR and C-reactive protein – CRP) in RA patients. The elevated level of MMP3 is associated with radiological changes in joints and can also be a predictor of severe destructive lesions in RA patients. Evaluation of the MMP3 level can also be useful for monitoring the therapy effectiveness using both standard disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (GEBD). Thus, evaluation of MMP3 concentration is useful for assessing disease activity and efficacy of treatment with DMARDs and GEBD, as well as for predicting the severity of destructive changes in joints.

Objective: to specify the association between the levels of proinflammatory cytokines, such as tumor necrosis factor-а (TNF-а), interleukin-1 β (IL-1 β), and IL-6, and the presence and degree of depression and anxiety spectrum disorders (ADSDs) in patients with rheumatoid arthritis (RA). Subjects and methods. The investigation included 45 patients with a valid RA diagnosis. Their mean age was 45.5+3.09 years; the mean disease duration was 155.0+26.5 months. The authors determined RA activity with the DAS28 index; fatigue degree with the Fatigue Severity Scale (FSS), and pain magnitude with the Brief Pain Inventory (BPI). Mental disorders were diagnosed by a psychiatrist in accordance with the ICD-10 and DSM-IV, by applying a number of psychiatric and psychological scales and tests. The concentration of proinflammatory cytokines was measured using the xMAP (27-plex) technology on a BioPlex-200 analyzer (Bio-Rad, USA). Results. There were mental ADSDs in 82.2% of the patients and moderate cognitive impairments (CI) in 67.7%. 80% of the examinees reported clinical fatigue; 64.5% experienced severe and moderate pain. The levels of TNF-а and IL-1s were slightly higher in patients with ADSDs and CI than in those without these disorders. The concentration of IL-6 was highest in the presence of anxiety disorders. However, these differences were statistically insignificant. The level of TNF-а was somewhat higher in patients with clinical fatigue and significantly higher in those who experienced intense pain. That of IL-1s was significantly higher in patients with severe and moderate pain than in those with mild pain (p < 0.05). Conclusion. ADSDs and CI in patients with RA are associated with the elevated levels of proinflammatory cytokines (TNF-а, IL-1s, and IL-6), which confirms the implication of chronic inflammation in the pathogenesis of these conditions in RA. High TNF-а and IL-1s levels are typical of RA patients with clinical fatigue and marked pain.

Subjects and methods. 102 patients with early RA (79 women and 23 men; median age 51 years [41 to 62, 25th to 75th percentile]; disease duration 4 months [2.5 to 6.0]; DAS28 5.4 [4.1 to 5.9]) were examined. A comparison group consisted of 616 patients including 27 with systemic lupus erythematosus, 15 with Sjo gren’s syndrome, 25 with ankylosing spondyloarthritis; 33 with osteoarthritis, 20 with overlap syndrome, 9, 22, and 168 patients with gouty, psoriatic, and undifferentiated arthritis, respectively; as well as 297 healthy donors matched with the examinees for gender and age. The concentrations of 36 biomarkers were measured by an immunonephelometric method, enzyme immunoassay, and xMAP technology. The values of one variable from others were predicted using a multiple linear regression method (multivariate analysis). Results. The strongest predictors of early RA, such as the concentrations of interleukin-6, C-reactive protein, granulo-cyte-macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN^-inducible protein, anti-cyclic citrullinated peptide antibodies, were identified and a candidate for MDI was developed for early RA (MIRRA). After thorough validation, MIRRA may be regarded as a precision serological assay for the early diagnosis of RA. Conclusion. The development of MDI having a higher diagnostic precision than routinely used biomarkers is imperative for early RA diagnosis that allows one to initiate active antirheumatic therapy that is able to effectively delay progressive joint injury.

Objective: to evaluate the clinical efficiency of tocilizumab (TCZ) versus rituximab (RTM) therapy using DAS 28, SDAI, and CDAI scores and to estimate remission rates using DAS 28 and the remission criteria proposed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) in 2011. Subjects and methods. Seventy-six patients with rheumatoid arthritis (RA) divided into 2 groups were examined. Group 1 included 42 patients receiving six TCZ infusions in an intravenous dose of 8 mg/kg at a 4-week interval during stable therapy with disease-modifying antirheumatic drugs (DMARDs) and glucocorticosteroids (GC); Group 2 comprised 34 persons who were given two RTM infusions in intravenous doses of 500 and 1000 mg at 2-week interval during therapy with DMARDS and GC in 12 (35%) and 22 (65%) patients, respectively. The EULAR criteria and SDAI and CDAI scores were used to evaluate therapeutic effectiveness. Remission was assessed using the EULAR criteria and the new 2011 EULAR/ACR remission ones. Results. In Group 1, the baseline DAS 28, SDAI, and CDAI scores were 6.44 [5.87; 7.04], 45.0 [36.2; 57.0], and 41.5 [32.0; 53.0]; in Group 2, these were 6.12 [5.52; 6.81], 34.3 [23.8; 45.9], and 31.3 [21.8; 38.5], respectively. At week 24 of therapy, Groups 1 and 2 patients achieved a DAS 28 remission in 71 and 23.5% of cases, a SDAI remission in 31 and 14.7%, and a CDAI remission in 33 and 17.6%, respectively. In the RTM-treated patients who had not previously received therapy with genetically engineered biological agents (GEBAs), DAS 28, SDAI, and CDAI remissions were observed more frequently (38, 23.8, and 28.6%, respectively) than in those receiving GEBAs (0%; p < 0.01) and their rate was comparable with that in Group 1 patients (according to SDAI and CDAI scores). In Groups 1 and 2, the remission rates according to the 2011 ACR/EULAR criteria were 24 and 11.8%, respectively. Conclusion. The results obtained during a 24-week trial are indicative of the high clinical efficiency of TCZ and RTM therapy. The number of TCZ-treated patients who had achieved a DAS 28 remission were much more while SDAI and CDAI remission rates among the patients who had not previously received GEBAs were virtually comparable with those when TCZ and RTM were administered.