Despite considerable advances in the control of acute rheumatic fever (ARF), the problem of this disease remains relevant and contains a number of unsolved issues as before. The paper displays an epidemiological update on ARF and analyzes a number of provisions of the recent (2015) American Heart Association guidelines on the revision of the Jones diagnostic criteria. The wide discussion in the academic circles concerns the clinical aspects of ARF (carditis, chorea), an understanding of which makes it possible to correctly predict the course of the disease, but also to form a rational therapy policy that affects its outcome. Current approaches to primary and secondary prevention of ARF are given; emphasis is placed on the necessity of designing a novel vaccine against Streptococcus.

The problem of the early diagnosis of rheumatoid arthritis (RA) remains relevant, which is associated with the limited potential of available biomarkers and the heterogeneity of the disease. Chemokines and cytokines produced by the synovial membrane of the patients play a leading role in the pathogenesis of the disease, suggesting that they may be used as promising biomarkers.

Objective: to comparatively investigate the relative mRNA expression of the homeostatic chemokines: stromal cellderived factor 1 (SDF-1/CXCL12), B-cell-attracting chemokine-1 (BCA-1/CXCL13), their receptors CXCR4 and CXCR5, the proinflammatory chemokines: macrophage chemotactic protein-1 (MCP-1/CCL2), T cell expressed and secreted chemokine on activation (CCL5/RANTES), interleukin-8 (IL-8) (IL-8/CXCL8), IL-17, and vascular endothelial growth factor (VEGF) in the synovial membrane biopsy specimens from patients with RA or osteoarthritis (OA) and from healthy individuals and to estimate the diagnostic informative value of these biomarkers.

Subjects and methods. The expression of mRNA was estimated using a real-time polymerase chain reaction assay. The RA group included 28 patients, their median age was 47 [35; 54] years; disease duration – 8 [4; 12] years; DAS28 – 4.9 [3.9; 5.5]; 16 and 14 patients were seropositive for rheumatoid factor and anti-cyclic citrulinated peptide antibodies, respectively. The OA group comprised 22 patients whose median age was 70.5 [61; 74] years. Fifteen clinically healthy individuals with a median age of 45 [28; 64] years were also examined.

Results and discussion. The RA group was noted to have significantly higher RANTES, IL-8, IL-17, VEGF, BCA-1, and CXCR5 mRNA levels than the OA group and healthy individuals. In the patients with OA, the level of the homeostatic chemokines BCA-1 and SDF-1, which had B-cell chemoattractant activities, was higher than that in the control group, which may suggest that they are implicated in the pathogenesis of the disease. The determination of RANTES mRNA expression was most informative in diagnosing RA: the area under the curve (AUC), 0.91 [95% confidence interval (CI), 0.84–0.99]; diagnostic sensitivity, 72.97% (95% CI, 55.88–86.21), diagnostic specificity, 96.15% (95% CI, 80.36–99.90); positive likelihood ratio (LR+), 18.95; negative likelihood ratio (LR-), 0.28 at a diagnostic threshold of 0.0350, so was CBC1 mRNA. The AUC for BCA-1 was 0.78 (95% CI, 0.66–0.89); diagnostic sensitivity, 56.25% (95% CI, 37.66–73.64), diagnostic specificity, 92.59% (95% CI, 75.71–99.09); LR+, 7.59; LR-, 0.47 at a diagnostic threshold of 0.0184.

Objective: to evaluate the impact of therapy with chondroitin sulfate (CS) and glucosamine (GA) on the clinical manifestations of low back pain (LBP).

Subjects and methods. A multicenter open-label observational prospective study was conducted in 22 cities of Russia (46 centers) to investigate the efficacy of a combination of CS and GA in the outpatient treatment of nonspecific LBP. A total of 9761 patients were enrolled in the study that was completed by 8546 patients. Therapeutic efficiency was evaluated from changes in pain intensity during movement and at rest, by using the visual analogue scale. The Oswestry disability index, an global physician and patient assessment of therapeutic efficiency, and a daily need for nonsteroidal anti-inflammatory drugs (NSAIDs) were taken into account as additional criteria for efficiency evaluation.

Results and discussion. The multicenter open-label observational study established the efficacy of a combination of CS and GA in treating nonspecific LBP: relief in pain during movement and at rest, functional improvement, and a reduction in the daily need for NSAIDs. The patients and physicians highly assessed therapeutic efficiency. The combination of CS and GA was also noted to be well tolerated. The findings may suggest that this combination may be a promising tool to treat LBP and gives proof to the expediency of its use in randomized placebo-controlled studies.

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.

Therapy for systemic lupus erythematosus (SLE) remains challenging. The long-term use of glucocorticoids (GC) and cytostatics considerably improves life expectancy, but at the same time favors the development of irreversible organ damages. To evaluate the efficacy of belimumab (BLM), a biological agent, that blocks B-lymphocyte-stimulating factor registered for the treatment of active SLE, is an important task of the practice of rheumatology.

Objective: to evaluate the efficacy and safety of BLM in patients with high and moderate SLE activity.

Subjects and methods. The investigation enrolled 16 patients with a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) score of 6 to 19, who were positive for antinuclear factor (100%) and had low complement levels and high anti-native DNA antibodies (81%). BLM was used as monthly intravenous infusions at a dose of 10 mg/kg. The efficiency and safety of the therapy were evaluated monthly and 1 year after the initiation of treatment with BLM; SLE activity was estimated using SLEDAI-2K; a physician’s global assessment of disease activity on a visual analogue scale (VAS); anti-DNA antibody level changes, complement levels, a GC dose, damage index, and adverse events were determined.

Results and discussion. BLM therapy proved to be effective in 62% of cases at 1 year after therapy initiation. At 1 month, SLE activity significantly decreased with SLEDAI-2K score diminishment from 9.31±3.21 to 6.25±2.80 in the entire group (p < 0.04). Over a month, the physician’s global assessment of disease activity significantly reduced from 19.25±6.60 to 13.68±3.97 mm (р<0.01) and reached minimum (8.28±6.87 mm) by 10 months of therapy. There was a significant decrease in anti-DNA antibodies and an increase in complement C4 level at 5 and 3 months of therapy, respectively. Six of the 10 patients who had received a complete cycle of BLM therapy achieved remission at 12 months. The dose of GC was significantly reduced at 6 months of therapy. Adverse events were rare. BLM was discontinued because of its inadequate efficacy in 4 patients.

Conclusion. Twelve-month therapy with BLM is effective in patients with high and moderate SLE activity according to SLEDAI-2K and with high immunological activity. The use of BLM in SLE contributes to a GC dose reduction and fails to cause serious adverse events.

Objective: to investigate the impact of treatment with subcutaneous methotrexate (MTX) and combined therapy with MTX and biological agents (BA) on the serum level of matrix metalloproteinase 3 (MMP3); to estimate the informative value of determination of MMP3 levels for predicting the clinical efficiency of therapy for early rheumatoid arthritis (RA).

Subjects and methods. A total of 45 patients with early RA were examined. In all the patients, MTX as the first disease-modifying anti-rheumatic drug was subcutaneously injected at a dose of 10 mg/week with its rapid escalation up to 20–25 mg/week. When the efficacy of MTX was inadequate, a BA was added [82% of the patients received adalimumab, 13% – abatacept, and 5% – other BA]; the follow-up duration was 1 year. Serum MMP3 levels were measured using an enzyme immunoassay before, 12 and 24 weeks after initiation of therapy.

Results and discussion. After week 52 16 patients continued to receive monotherapy with subcutaneous MTX; BA were added to therapy in 29 patients in different follow-up periods. In the patients with early RA, the baseline MMP3 level was significantly higher than that in healthy donors: 46.7 [15.5; 64.5] and 7.74 [5.5; 11.8] respectively (p < 0.05). In the entire group, the level of MMP3 significantly declined after 12 and 24 weeks of therapy when it was 23.7 [1.5; 44.5] and 3.25 [0.025; 29.0], respectively. 16 patients who responded well to MTX after 52 weeks of therapy showed lower baseline inflammatory activity: (DAS28, 4.4 [4.4; 5.7], SDAI, 24.1 [16.9; 35.7], and CDAI, 20.7 [15.8; 30.0]) and MMP3 levels (10.6 [0.03; 38.1]) than those in 29 patients receiving the combined therapy: 6.05 [5.3; 6.7], 40.7 [26.7; 48.2], 35.8 [23.5; 42.8], and 58.8 [27.0; 106.3], respectively (p < 0.05). ROC analysis established that the baseline MMP3 level of > 54.6 ng/ml and the persistent higher level of this parameter 12 weeks after the initiation of treatment with MTX (> 25.1 ng/ml) were associated with lack of efficiency of MTX monotherapy after 52 weeks and with the necessity of using combined therapy [area under the curve (AUC), 0.78; 95% confidence interval (CI), 0.63–0.93 and AUC, 0.96; 95% CI, 0.54–0.86, respectively].

Conclusion. The high baseline MMP3 level (> 54.6 ng/ml) and the persistent increased level of this parameter 12 weeks after initiation of therapy with subcutaneous MTX (> 25.1 ng/ml) may be regarded as a likely predictor for the inefficiency of MTX monotherapy and for the necessity of using BA.

Objective: to assess a risk for new fractures in a cohort of postmenopausal women who have sustained low-trauma fractures, by using the FRAX® algorithm, and to compare the assessments with data on the fractures have occurred during a prospective follow-up study.

Subjects and methods. The investigation enrolled 128 postmenopausal women (mean age, 64.9±8.3 years) who had sustained low-trauma fractures at five sites (the hip, forearm, humeral neck, vertebral column, and ankle). A ten-year fracture risk was assessed using the FRAX® algorithm with and without regard for bone mineral density (BMD). New osteoporotic fractures were recorded during a three-year prospective follow-up study.

Results and discussion. The average FRAX® algorithm values for all new osteoporotic and hip fractures in the entire group were 18.0±5.6 and 3.7±3.7% (without consideration of BMD), 17.9±6.6 and 3.5±4.0% (with consideration of BMD) (p > 0.05). The true incidence of recurrent fractures over 3 years was 17.2%. During 3 years, the incidence of recurrent fractures in the women who had sustained low-trauma fractures of the proximal hip, humeral neck, and spinal column was 28.6, 25.0, and 22.8%, respectively, which exceeded the estimated 10-year fracture risk for these sites. The history of multiple low-trauma fractures versus single one increased the risk for subsequent fractures by 3.63 and 9.43 times among women with high or low estimated FRAX risk rate, respectively.

Conclusion. The three-year prospective follow-up study has shown that the FRAX® algorithm underestimated the risk associated with the presence of recurrent fractures in the history; moreover, new fractures significantly more commonly occur in persons who have sustained low-trauma fractures in the proximal hip, humoral neck, and vertebral column.

Genetic factors that are an important hereditary component determining a predisposition to osteoporosis (OP) are 60–80% responsible for bone mineral density (BMD). Some polymorphic genes have been previously shown to affect the efficiency of performed anti-osteoporotic therapy.

Objective: to study the impact of farnesyl diphosphate synthase (FDRS) and geranylgeranyl diphosphate synthase (GGSPI) gene polymorphisms on BMD changes during 12-month therapy with bisphosphonates (BP) in women with postmenopausal OP.

Subjects and methods. The investigation enrolled 53 women with OP. Spine and proximal femur BMD was determined using X-ray densitometry before and after BP treatment. The -99A/C and -8188T ins/del polymorphisms in the FDPS and GGPS1 genes were investigated using real-time polymerase chain reaction.

Results and discussion. The BMD changes were less marked in women with the C allele of C/T -99/C polymorphism in the FDPS gene than those in carriers of the genotype AA: 2.3±3.6 and 4.4±3.8% (р = 0.062) in the spine; 0.6±3.1 and 2.8±4.5% (р = 0.075) in the femoral neck; 0.5±2.9 and 2.5±2.8% (р = 0.020) in the entire femur, respectively. Femoral neck densitometry showed a significantly weaker response to BP treatment in the patients carrying the mutant genotype del/del of GGSP1 -8188T ins/del polymorphism than in those with the wild-type genotype ins/ins (0.8±4.2 and 4.1±2.5%, respectively; р = 0.030). No significant differences for this polymorphism were found in other areas of BMD measurement.

Conclusion. The described pilot study has indicated that the examined FDPS and GGSP1 gene polymorphisms may be predictors for a response to BP therapy in patients with OP. Further investigations that will contribute to the choice of the most effective therapy for this disease are needed to confirm our results.

As of now, magnetic resonance imaging (MRI) ranks high in the early diagnosis of inflammatory changes in the musculoskeletal system. The uniqueness of MRI is that this diagnostic technique can detect the signs of active and inactive inflammation at the pre-radiological stage of the disease, i.e. before the onset of radiological symptoms of sacroiliitis and the formation of spinal syndesmophytes. At the same time there is evidence that there is a temporary association between active inflammation and the development of radiological changes in the joints.

The detection of bone marrow edema in the subchondral portions of bone tissue is of great importance not only for diagnosing the disease and verifying inflammatory activity, but also for predicting the development of chronic arthritis, choosing a treatment option, and evaluating the efficiency of performed therapy.

Based on their long-term experience, the authors provided explanations of the MRI pattern of active and inactive chronic sacroiliitis and spondylitis, which can considerably facilitate the early diagnosis of injury to the sacroiliac joints and vertebral column in patients with ankylosing spondylitis.

According to the predominant mechanisms of immunity activation, human inflammatory diseases are divided into two main categories: autoimmune and autoinflammatory ones. At the same time, the autoimmune and autoinflammatory diseases have much common in both the range of clinical manifestations and trigger environmental, epigenetic, and genetic factors, inflammatory mediators, tissue damage, and approaches to pharmacotherapy. The hyperproduction of the proinflammatory cytokine interleukin 1 (IL-1) is supposed to largely determine the cross between autoimmunity and autoinflammation, which is characteristic of many immunoinflammatory diseases. The study of a role of IL-1 in regulating an interaction between innate (Toll-like receptor activation, inflammasomes) and adaptive (Th1 and Th17 immune responses) immunities and efficiency of IL-1 inhibitors may be of great importance in interpreting the pathogenetic mechanisms of human immunoinflammatory diseases and elaborating novel approaches to personified therapy.

Despite great advances in the study of the pathogenesis of rheumatoid arthritis (RA), which could design a radically new class of fundamentally sound therapeutic agents, many immunological aspects remain fully unstudied. The role of innate immunity mechanisms in the development of autoimmune inflammation is one of the important issues in the pathogenesis of not only RA, but also all rheumatic diseases. The discovery of pattern recognition receptors (PRRs) has allowed fundamental immunology to make a great stride toward understanding how these mechanisms are implemented. The study of membranous and endosomal Toll-like receptors (TLRs), the most extensive and well-studied group of PRRs, is a promising area of modern rheumatology. It is significant to note that some molecular agents, the presence of which in tissue is associated with its damage, are able to stimulate TLRs. They have received the name damage-associated molecular patterns (DAMPs). The paper provides a review of the literature on the mechanisms of TLR-mediated signaling pathways, on different aspects of a role of individual TLRs and DAMPs in the induction and maintenance of autoimmune inflammation in RA, and on prospects for targeted therapy aimed at inhibiting some TLRs and DAMPs.

The purpose of the review is to clinically evaluate circulating autoantibodies in systemic sclerosis (SS). The diseasespecific, i.e. disease-associated, antinuclear autoantibodies: to centromeres, to topoisomerase 1; a group of antinuclear antibodies to ribonucleoprotease III, Th/T0, Pm/Scl, as well as autoantibodies to ribonucleoproteins U1 RNP and U3 RNP are considered in detail. The detection rate of the antinuclear autoantibodies is high (90–95%); at the same time, each of the autoantibodies is detectable separately in a small number of patients with certain clinical presentation, patterns of the course, and prognosis and has clear genetic associations. There is a clear association between the type of autoantibodies, the nature of organic complications, and survival rates. Specific autoantibodies belong to predictors for the course of the disease and its outcome. How much the clinical distinctions between the subgroups reflect pathogenetic differences in immune dysregulation remains unclear. SS-specific autoantibodies emerge in the earliest stage of the disease until the clinical picture of the disease becomes extensive. Their diagnostic value and place in the 2013 new classification criteria for the disease are described in detail. There is evidence that it is important to introduce the determination of anti-centromere, anti-topoisomerase autoantibodies and anti-RNA proteinase III antibodies into clinical practice. The detection of the latter is essential due to the importance of identifying a special subtype of SS, which has a potentially poor prognosis, among other factors, due to the increased incidence of cancers. When making the SS diagnosis, it is appropriate to indicate its positivity for main scleroderma autoantibodies.

The last section of the review deals with the non-specific autoantibodies directed against targets, such as endothelial cells and fibroblasts, functional molecules (different cell receptors), extracellular matrix proteins, enzymes, etc. A number of interesting hypotheses and theories, which explain the initiating role of this subgroup of autoantibodies in the occurrence and development of SS, are considered.

The paper gives the data available in the literature on the role of opportunistic microorganisms (OMs) in rheumatic diseases (RDs). OMs are anticipated to be involved as triggers initiating the development of chronic inflammation. Along with this, OMs in autoimmune diseases may play a defensive role through the interaction with Toll-like receptors and the activation of T cells that have suppressor activity. The possible involvement of OMs in the pathogenesis of RDs provides support not only the isolation of microorganisms, but also the detection of antibacterial antibodies of different classes. Of great importance are OMs in the etiology of comorbid infections, the risk of which is due to both the presence of autoimmune RDs and the necessity of using the drugs having immunosuppressive activity. The active clinical introduction of biological agents is followed by a rise in the rate and severity of different infections, including those caused by OMs. Having a marked biological and environmental plasticity, OMs are able to persist long when there are changes in the immune defense of patients with RDs. There is evidence for the higher adhesive properties and persistent potential of the microorganisms that colonize the body of patients with RDs. In the latter, OMs that are distinguished by pronounced antibiotic polyresistance are isolated, making the treatment and prevention of opportunistic infections more difficult in rheumatology. The results of the papers analyzed in the review suggest that the study of OMs in RDs is of practical importance.

The paper describes a clinical case of recurrent microscopic polyangiitis diagnosed 10 years after kidney allotransplantation that was accompanied by the hyperproduction of antibodies to myeloperoxidase, graft damage with the morphological picture of pauci-immune extracapillary glomerulonephritis with crescents and other systemic manifestations, including interstitial lung injury complicated by hemoptysis. An effect is produced by biological anti-B-cell therapy with rituximab. The discussion involves the detailed review of the literature.

Minutes of the Meeting of the Special-Purpose Committee of the Expert Council of Rheumatology, Ministry of Health of the Russian Federation No. 15 dated October 24, 2015.

List of measures in rheumatology in 2016.