The paper gives the latest data on the impact of traditional cardiovascular risk factors, chronic inflammation, antirheumatic therapy (disease-modifying antirheumatic drugs and biological agents) on the cardiovascular system. 

In 2015, guidelines for the diagnosis and treatment of eosinophilic granulomatosis with polyangiitis, formerly known as Churg-Strauss syndrome, were prepared with the participation of experts from 5 countries of Europe, the USA, and Canada, who accumulated scientific achievements and currently gained clinical experience. The proposed guidelines should not be regarded as final standards, but must become a guide for the selection of a personification strategy for managing patients with eosinophilic granulomatosis with polyangiitis and serve as a starting point for further investigations. The purposes of the publication are general characterization of the key points of the guidelines and discussion of some debate problems. 

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.

Systemic lupus erythematosus (SLE) is characterized by the pathological activation and differentiation of B lymphocytes. The B-lymphocyte stimulator (BLyS), also known as B cell-activating factor of the tumor necrosis factor family (BAFF), and its homologue, a proliferation-inducing ligand (APRIL), belong to the ligands of the tumor necrosis factor (TNF) family and play a key role in B-lymphocyte selection and survival.

Objective: to determine serum BAFF and APRIL concentrations in patients with SLE and a relationship of the clinical and laboratory parameters of the disease to the level of these cytokines.

Subjects and methods. The investigation enrolled 73 patients (62 women and 11 men; median age, 30.0 [28.0; 46.0] years) with SLE (disease duration, 5.0 [1.5; 11.0] years) and its high activity (the median SLEDAI-2K scores of 8 [2; 13]).

Involvement of the kidneys and joints were found in 40 and 36% of cases, respectively; there were hematologic disorders in 38%, antinuclear factor (ANF) in 94.5%, and anti-double stranded DNA antibodies in 77%. The concurrent antiphospholipid syndrome was detected in 15% of the patients. 66% of the patients took glucocorticoids (GCs) (the median dose was 10 [0; 15] mg/day, calculated with reference to prednisolone), 42% received cytotoxic drugs (cyclophosphamide, mycophenolate mofetil, azathioprine); 12% used biological agents (BAs); 31.5% received no therapy at enrolment in the investigation. Serum BAFF and APRIL concentrations were estimated using an enzyme immunoassay.

Results and discussion. The concentrations of BAFF and APRIL did not differ essentially in the patients with SLE and in the controls: the median level of BAFF was 0.02 [0.01; 0.64] and 0.02 [0.01; 0.03] ng/ml; that of APRIL was 2.09 [0.01; 3.80] and 0.01 [0.01; 4.16] ng/ml, respectively. The elevated concentration of BAFF (>0.82 ng/ml) was revealed in 5.5% of the patients with SLE and that of APRIL (>5.96 ng/ml) in 4.1%. There was a positive correlation between the concentration of BAFF and the level of hematuria (r = 0.261; p < 0.05) and a negative correlation with hemoglobin concentrations (r = -0.289; p < 0.05), disease duration (r = -0.261; p < 0.05), and SLICC/DI scores (r = -0.286; p < 0.05). There was a positive correlation of APRIL levels with SLEDAI-2K scores (r = 0.323; p < 0.01), ANF titer (r = 0.256; p < 0.05), and K+ concentrations (r = 0.322; p < 0.05) and a negative correlation with hemoglobin levels (r = -0.299; p < 0.05), white blood cell count (r = -0.253; p < 0.05), and glomerular filtration rate (GFR) (r = -0.299; p < 0.05). The elevated concentrations of both BAFF and APRIL were found more often in patients with lupus nephritis compared to those without this condition (p < 0.05). The patients with SLE-induced hematological disorders had a higher APRIL concentration (p < 0.05) than those without these disorders; the groups proved to be comparable in BAFF levels. As SLE activity increased (SLEDAI-2K scores of ≥8), there was a rise in the concentration of both ligands (p < 0.05).

A subgroup of SLE patients (n = 26) who had received neither GCs nor other immunosuppressants or BAs was separately analyzed. In these patients, the concentration of APRIL was higher than that in the control group: 3.06 [2.09; 4.05] and 0.01 [0.01; 4.16] ng/ml (p < 0.05), there were no differences in the level of BAFF. There was a positive correlation between the level of APRIL and the concentration of creatinine (r = 0.635; p < 0.001), urea (r = 0.574; p < 0.01), and uric acid (r = 0.633; p < 0.001) and a negative correlation with the level of white blood cells (r = -0.437; p < 0.05), lymphocytes (r = -0.497; p < 0.05) and GFR (r = -0.663; p < 0.001). The BAFF concentrations correlated positively with hematuria levels (r = 0.591; p < 0.01), SLEDAI-2K scores (r = 0.413; p < 0.05), and erythrocyte sedimentation rate (r = 0.394; p < 0.05) and negatively with hemoglobin concentrations (r = -0.2488; p < 0.05) and GFR (r = -0.473; p < 0.05).

Conclusion. The concentrations of BAFF and APRIL were comparable in the patients with SLE and healthy donors. The elevated levels of both BAFF and APRIL were associated with high disease active (SLEDAI-2K scores of ≥ 8) and lupus nephritis; those of APRL are related to hematological disorders. Immunosuppressive therapy (GCs, cytostatic drugs, BAs) decreased the serum concentration of APRIL in patients with SLE. 

The genes, the high basic expression of which indicates the efficiency of methotrexate (MTX) therapy in relieving joint inflammation and destruction in patients with rheumatoid arthritis (RA), have been defined.

Objective: to find an association between the initial expression of the genes: mTOR (mammalian target of rapamycin), a major regulator of cell growth and proliferation; ULK1 (an autophagy marker 1); p21 (a cyclin-dependent kinase inhibitor); kaspase-3 (an apoptosis activity indicator); MMP-9 (matrix metalloproteinase 9), and cathepsin K, which are involved in joint destruction, and the cytokines: TNF-α (tumor necrosis factor-α), TGFβ1 (transforming growth factor β1) and Runx2 (Runt-related transcription factor 2) in the blood of RA patients with disease activity and joint destruction before and after MTX therapy during 24 months.

Subjects and methods. Forty patients (mean age, 47.5 years) with RA lasting < 2 years) and 26 healthy donors (mean age, 45.1 years) were examined. All the patients took MTX for 2 years. A clinical response was assessed with disease activity score (DAS28); erythrocyte sedimentation rate and the serum levels of anti-cyclic citrullinated peptide antibodies (ACCPA), C-reactive protein (CRP), and rheumatoid factor (RF) were also estimated. Joint destructive changes were assessed by radiography. Furthermore, blood and knee articular cartilage samples from 21 patients (mean age, 50.4 years) with late-stage RA and cartilage samples from 25 healthy individuals were investigated. Gene expression in the cells of peripheral blood and cartilage was determined by real-time reverse transcriptase polymerase chain reaction.

Results and discussion. MTX therapy considerably reduced disease activity assessed by DAS28, CRP levels, stiffness, tender and swollen joint counts (TJC and SJC); however, joint space (JS) narrowing (JSN) substantially increased compared with the baseline values. The expression of the ULK1, p21, MMP-9, cathepsin K genes, and TGFβ1 was increased both at the beginning of the investigation and 24 months later whereas the initially higher expression of mTOR, TNF-α, caspase 3, and Runx2 was decreased by the end of therapy to the level of the healthy individuals. The initial expression of the TGFβ1, Runx2, caspase 3, and р21 genes correlated negatively with the RF level measured both at the beginning of the investigation and 24 months later. There was a positive correlation of the initial expression of ULK1 and MMP-9 with CRP levels prior to therapy and that of the initial expression of MMP-9 with baseline DAS28 scores and NSJ. Moreover, the initial expression of the TNF-α gene positively correlated with JSN at the end of therapy and that of the p21, caspase 3, and Runx2 genes with a change in DAS28. There was also a negative correlation of the initial expression of the mTOR gene with the SJC and the number of erosions; the p21 and TNF-α genes correlated negatively with SJC and TJC; and the TNF-α, TGFβ1, Runx2, and cathepsin K genes also negatively correlated to the duration of stiffness at the end of therapy. A positive correlation was found between the expression of the cathepsin K and TGFβ1 genes in the blood and articular cartilage of patients with late-stage RA.

Conclusion. The expression of the MMP-9 and ULK1 genes is associated with disease activity. The high initial blood expression of the other examined genes is associated with the more effective action of MTX on stiffness (TNF-α, Runx2, cathepsin K, and TGFβ1), TJC and SJC (mTOR, p21, and TNF-α), and the progression of joint destruction (mTOR) and may play a protective role. The positive correlation of the blood and articular cartilage expression of the TGFβ1 and cathepsin K genes may point to their co-regulation in these tissues in RA.

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.

Angiotensin II, aldosterone, and fibroblast growth factor (FGF) stimulate neoangiogenesis, fibroblast proliferation, and elaboration of proinflammatory cytokines, which in turn contributes to increased pannus mass and the development of joint tissue destruction in rheumatoid arthritis (RA).

Objective: to establish the specific features of changes in the blood levels of angiotensin II, aldosterone, and FGF in patients with RA in relation to the duration and severity of the disease.

Subjects and methods. Examinations were made in 194 patients diagnosed with RA without comorbidity; the patients’ mean age was 47.7±10.2 years; the disease duration was 3.82±3.43 years. DAS28 scores for RA were calculated based on C-reactive protein levels. An enzyme immunoassay was used to determine the serum levels of anti-cyclic citrullinated peptide antibodies (ACCPA), angiotensin II, aldosterone, and FGF.

Results and discussion. All the examinees were ascertained to have increases in the concentration of angiotensin II and aldosterone in blood by twice and in that of FGF by 2.5 times compared to the controls (p < 0.05). In patients with a RA duration of < 2 years, the blood level of angiotensin II was 25% higher than in those with a RA duration of > 5 years and the concentrations of aldosterone and FGF in patients with long-term RA were twice as high as in those with early RA. In patients with high RA activity, the blood level of angiotensin II was 1.5-fold higher than in those with low and moderate disease activity (p < 0.05). In patients with a high blood ACCPA level, the concentrations of angiotensin II, aldosterone, and FGF were 20, 30, and 25%, respectively, higher than in those with low ACCPA levels. The correlation of DAS28 with blood angiotensin II levels increased with enhanced RA activity. The high aldosterone and FGF values in RA patients are associated with the progression of joint radiographic changes.

Objective: to evaluate of the efficacy of methotrexate (MTX) as a concentrated solution (50 mg/ml) for subcutaneous administration versus coated tablets at equal oral doses of 15 mg/week for rheumatoid arthritis (RA).

Subjects and methods. The study was conducted at two centers: the V.A. Nasonova Research Institute of Rheumatology and the Saint Petersburg Medical Academy of Postgraduate Education, Federal Agency for Healthcare and Social Development. At each center, the patients were randomized into two groups: a study group and a control group. In the study group, MTX was used as a concentrated solution (50 mg/ml) for subcutaneous administration at a dose of 15 mg/week. The controls were patients with RA who took MTX as coated tablets once weekly at the same dose as used in the study group. A trend in the 28-joint disease activity score (DAS28) was a main criterion for evaluating therapy efficiency. For efficiency evaluation, other criteria were additionally used; these included disease activity assessment by a physician; functional status assessment (Health Assessment Questionnaire); C-reactive protein level. The safety of the used MTX formulations was evaluated during each visit: the patients' subjective sensations and examination and laboratory findings were kept in mind.

Results and discussion. After randomization (totally at the two centers), the study group included 42 patients and the control group comprised 23. Based on 95% confidence interval for the mean, it may be concluded that the efficiency of MTX as a solution for subcutaneous administration (the study group) is no less than that of MTX as tablets (the control group). Subcutaneous MTX was shown to be associated with the lower rate of therapy correction than oral MTX; and did not differ from it in toxicity. In addition, subcutaneous MTX may noticeably reduce the need for biological agents.

The final DAS28 value in the study group does not exceed that in the control group (t-test). Remission was observed only after subcutaneous administration of the drug.

Conclusion. Based on the findings, it can be concluded that MTX as a concentrated (50 mg/ml) solution for subcutaneous administration may be the drug of choice for the treatment of patients with active RA.

The feature of rheumatoid arthritis (RA) is the predominant clinical picture of chronic synovial joint inflammation accompanied by progressive cartilage and bone destruction, the pathogenesis of which is greatly due to autoimmune mechanisms. Some investigations demonstrate that a set of poor climatic and geographical factors may influence the development of immune disorders that are a trigger in the development of RA.

Objective: to comparative analyze immunological parameters in RA in dwellers from different regions of Uzbekistan.

Subjects and methods. The study enrolled RA patients from three Uzbekistan zones: 1) Tashkent (n = 25), 2) Xorazm Region (n = 25); 3) Namangan Region (n = 28).

Results and discussion. Comparative analysis of the immune status indicated that the patients living in Zone 2 exhibited a significantly reduced T cell immune response (p < 0.05), a considerably higher count of B lymphocytes (p < 0.001), and significantly lower levels of CD11b+, CD18+, CD25+, and CD95+ cells (p < 0.05) than did those from the two other zones. Examination of the frequency of the monomorphic determinant of histocompatibility Class I (HLA-I) antigens revealed its significant decrease in the patients residing in Zones 1 and 3 (p < 0.05) whereas the RA patients from Zone 2 had a significantly higher frequency of HLA-DR (p < 0.05).

Conclusion. The comparative analysis shows that the immunological parameters differ in the patients from the three zones of Uzbekistan, which may suggest that the climatic and geographical factors of the environment may influence the course of the disease.

Osteoporosis (OP) is one of the most common diseases and is characterized by serious clinical manifestations such as low-energy bone fractures that cause severe social consequences. In this connection, OP is now receiving much attention worldwide. In Yaroslavl, the Department of Therapy (Head, Professor N.I. Korshunov, MD), Institute of Postgraduate Education, Yaroslavl State Medical University (Chancellor, Prof. A.V. Pavlov, MD), has been intensively conducting researches into different aspects of OP for more than 20 years. The main areas of the investigations performed are the issues of the epidemiology and outcomes of osteoporotic fractures, the relationship of OP to different diseases (rheumatoid arthritis, cardiovascular diseases), as well as the specific features of the development of OP in fertile men and women and the problem of calcium and vitamin D deficiency in pregnant women. 

The lecture considers the problem of rare systemic connective tissue diseases, such as idiopathic inflammatory myopathies (IIMs). It underlines the clinical and immunological heterogeneity of their subtypes, which defines therapeutic tactics and prognosis. The diagnostic criteria for IIMs are given. A differential diagnostic algorithm based on the exclusion of phenotypically similar forms of myopathies of different genesis is proposed. 

There have been now prerequisites for changing the scientific view of the etiology and pathogenesis of spondyloarthritis (SpA). An important role is assigned to the dysfunction and disintegration of the so-called barrier organs that make protection of man between his internal milieu and the environment. An update on cellular and molecular mechanisms in the pathogenesis of SpA permits rheumatologists to offer a hypothesis of the concept of barrier organ disease as a preclinical stage of the diseases included in the SpA group. There is reason to think that this process involves individual genetic and immune factors leading to damage of the superficial epithelium of the mucosal membranes and epidermis that serves as the first protective barrier for innate immunity and is in contact with huge numbers of microorganisms (a microbiome) and with the pathogen-associated molecular patterns. The microbiome may affect the preclinical phase of the disease in several ways, including those to change the composition of the microflora (dysbiosis) and to act as targets for immunological dysregulation. 

Systemic lupus erythematosus (SLE) is one of the most severe and prognostically poor systemic connective tissue diseases that affect mainly women of childbearing age. The recent researches have provided a deeper insight into its pathogenesis, the identification and definition of a role of cytokines, cells, and intercellular bonds involved in the development of SLE. These data are borne in mind when designing novel biological agents, the action of which is aimed at inhibiting the targets implicated in the development of the disease. This information also may provide better understanding the mechanism of action of drugs, such as belimumab and rituximab, which have already proven their efficacy. 

The vitamin K antagonist warfarin is an essential medicine from a group of anticoagulants, which is used to treat antiphospholipid syndrome (APS). However, it has a number of disadvantages especially in patients who need longterm and frequently lifetime prevention of thromboses. New oral anticoagulants, such as dabigatran etexilate (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis) and others, have been recently synthesized. Unlike warfarin, they are administered at fixed doses, require neither routine monitoring nor diet, and interact with drugs only in small amounts. The new oral anticoagulants have been approved for certain indications, but the data of performed trials are inapplicable to patients with APS. These medicines are expected to improve quality of life in patients with this condition. 

Dermatomyositis (DM) and polymyositis (PM) belong to idiopathic inflammatory myopathies (IIM) and are characterized by inflammatory injury to the skeletal muscles. In DM, unlike PM, there is skin injury that serves as a pathognomonic sign of this condition. Panniculitis (PN) is one of the rare cutaneous manifestations in this disease.

Objective: to investigate the clinical and laboratory characteristics of IIM accompanied by PN and to elaborate guidelines for managing these patients.

Subjects and methods. Examinations were made in 318 patients (75 men and 243 women) aged 18 to 80 years who were diagnosed with IIM (mean disease duration of 18.97±7.4 months) and followed up at the V.A. Nasonova Research Institute of Rheumatology in 1996 to 2015.

Results and discussion. In 12 (3.8%) of the 318 patients, lobular PN that was associated with the diagnosis of DM verified in all cases. The clinical picture in this patient group was also characterized by skin injury as erythema on the face and trunk and Gottron’s papules (100%), periungual capillaritis (91.7%), ulceronecrotic vasculitis (57.3%), periorbital edema (75%), fever (41.7%), alopecia (50%), and joint involvement (25%).

Conclusion. The development of PN is associated with the acute period of DM and the emergence of new foci is related to an exacerbation of this disease, which requires active therapy. 

The paper deals with an experimental study of prophylactic reinforcement of the proximal femur in old patients suffering from various diseases that induce destructive and dystrophic changes in bone tissue and cause pathological fractures. The authors have developed a prophylactic reinforcement procedure and created the designs of original implants for its performance with the patents of the Russian Federation having been obtained. The performed mathematical modeling and bed tests of the strength of a reinforced bone-implant system prove the increased strength of the proximal femur by 23–93% and lower the risk of fracture in the occurrence of low-energy injury.