The widespread introduction into clinical practice of modern approaches to the treatment of rheumatoid arthritis (RA), the rational use of traditional and targeted antirheumatic drugs can effectively suppress inflammatory activity, restrain the progression of the disease and improve the quality of life of patients. At the same time, in some patients, even after the repeated change of targeted drugs, it is not possible to achieve the target level of RA activity. Serious difficulties arising in the management of such patients raised the question of identifying a special variant of the disease – difficult-to-treat (D2T) RA. The presence of various variants of D2T RA and the need to use a personalized approach to therapy justify the creation of special recommendations for the management of this category of patients. The first step in preparing these recommendations was the definition of D2T RA recently presented by the EULAR working group. It includes three criteria: 1) insufficient effectiveness of the therapy; 2) the presence of an active symptomatic disease; 3) clinical perception.

Objective: to evaluate the expression of interferon-stimulated genes (ISG) – interferon (IFN) signature – in patients with rheumatoid arthritis (RA) and its dynamics during anti-B-cell therapy.
Patients and methods.We examined 20 patients with RA who received two infusions of the biosimilar rituximab (RTM) Acellbia® in a total dose of 1200 mg. Five genes were selected to evaluate IFN signature: IFI44L, MX1, IFIT1, RSAD2, EPSTI1. The expression of IFI44L and IFIT1 could not be determined for technical reasons, and further analysis included three genes – MX1, EPSTI1, RSAD2. IFN signature was calculated as the average value of the expression of three selected genes (IFN-score).
Results and discussion. The initial expression level of MX1 was 11.48 (5.45–19.38), EPSTI1 – 12.83 (5.62–19.64), RSAD2 – 5.16 (2.73–10.4) and IFN-score –10.3 (5.18–17.12), in patients with RA it was statistically significantly higher than in healthy donors: 1.26 (0.73–1.6); 1.06 (0.81–1.48); 0.93 (0.72–1.19) and 1.09 (0.92–1.42), respectively (p<0.05). The IFN-score was high in 15 (75%) patients, low in 5 (15%). The use of RTM was accompanied by a statistically significant decrease in disease activity and the level of acute phase parameters (ESR, CRP) after 12 and 24 weeks of therapy (p<0.05). In the group as a whole, as well as in patients with a moderate effect of therapy or its absence, by the 24th week of treatment, an increase in the expression of RSAD2 (p<0.05) and a tendency to an increase in the IFN-score level (p=0.06) were observed.
Conclusion. In patients with RA, an increased expression of ISH was found compared to healthy donors. An increase in the expression of RSAD2 and IFN-score is observed both in patients with a satisfactory effect of RTM and with no effect. The obtained results can be important for predicting the course of the disease and personalizing therapy.

The role of antiphospholipid antibodies (aPL), which are not included in the classification criteria, in antiphospholipid syndrome (APS) and
systemic lupus erythematosus (SLE) is not well understood.
Objective: to determine the frequency of detection of IgG antibodies to domain 1 of β₂-glycoprotein 1 (IgG-aβ₂GP₁-D₁), IgA antibodies
to cardiolipin (aCL) and IgA antibodies to β₂-glycoprotein 1 (IgA-a β₂GP₁) in patients with primary APS and APS in combination with
SLE.
Patients and methods. The study included 63 patients in whom IgG/IgM-aCL and IgG/IgM-aβ₂GP₁ were detected by enzyme-linked
immunosorbent assay (ELISA) and IgG/IgM/IgA-aCL, IgG/IgM/IgA-aβ₂GP₁ and IgG-aβ₂GP₁-D₁ by chemiluminescence analysis (CLA).
Results and discussion. The detection rate of IgG-aβ₂GP₁-D₁ was 76%, IgA-aCL – 56%, IgA-aβ₂GP₁ – 48%. Isolated positivity for IgA-aCL,
IgA-aβ₂GP₁, IgG-aβ₂GP₁-D1 was not observed. The presence of IgA-aCL, IgA-aβ₂GP₁, IgG-aβ₂GP₁-D₁ was associated with high positivity for
IgG/IgM-aCL and IgG/IgM-aβ₂GP₁. There was a statistically significant relationship between IgA-aCL/IgA-aβ₂GP₁ and the standard aPL
profile, as well as IgG-aβ₂GP₁-D₁, IgG-aCL and IgG-aβ₂GP₁.
Conclusion. A high detection rate of IgG-aβ2GP₁-D₁, IgA-aCL, IgA-aβ₂GP₁ was found in patients with APS. A statistically significant relationship
was found between IgA-aCL/IgA-aβ₂GP₁ and the standard aPL profile, as well as IgG-aβ₂GP₁-D₁ with IgG-aCL and IgG-aβ₂GP₁.

Objective: to study in dynamics metabolic changes in lymphocytes on the model of adjuvant-induced rheumatoid arthritis (RA) in warm-blooded animals.
Material and methods. The RA model was elicited by administering Freund's complete adjuvant (AF) to male Wistar rats. Lymphocyte metabolism was corrected with a mixture of citric and succinic acids, which was injected for 4 weeks (at doses of 17 and 88 mg/kg body weight) from the first day of model formation. Animals of the control group were injected subcutaneously with isotonic sodium chloride solution. The total number of leukocytes, the size of lymphocytes and the activity of lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH) in these cells were determined. Changes in the musculoskeletal system were assessed radiographically and actometrically in the «open field» model.
Results and discussion. In the first 2 weeks of the experiment in the model group, an increase in the level of leukocytes by 65% compared to the control (p=0.002) was noted, an increase in the activity of lymphocytes SDH by 51% and a decrease in the total («horizontal») mobility of animals by 30% were also revealed. Subsequently, the level of leukocytes decreased by 25%, the activity of LDH and SDH – by 38%, the radius of lymphocytes – by 14% (p<0.01). The action of carboxylic acids was dose-dependent: at the maximum dose, no statistically significant differences in the total number of leukocytes, LDH and SDH activity in lymphocytes, as well as their sizes were found between the group with adjuvant- induced RA and the control group.
Conclusion. In animals with adjuvant-induced RA, correction of the metabolic status of lymphocytes with a mixture of citric and succinic acids, which are key substrates of the Krebs cycle, led to a decrease in structural damage of musculoskeletal system and, as a consequence, to the maintenance of normal range of motion.

To this date there have been no studies of subclinical atherosclerosis in the patients with calcium pyrophosphate crystal deposition disease (CPPD); in osteoarthritis (OA) such works are rare.
Objective: to assess the prevalence of subclinical atherosclerosis of carotid arteries (CA) in patients with CPPD and OA.
Patients and methods. The case-control study included 26 patients with CPPD and OA. The diagnosis of CPPD was based on the criteria of D.J. McCarty, diagnosis of OA was based on national clinical practice guidelines. We recorded data on smoking, blood pressure level. Assessed blood lipid spectrum, serum levels of glucose, creatinine, uric acid, CRP. Obesity was diagnosed in accordance with the WHO recommendations. All patients underwent CA Doppler ultrasonography (DUS). An increase in intima-media thickness (IMT) >0.9 mm was considered a manifestation of subclinical atherosclerosis. The SCORE index was calculated for all patients.
Results and discussion. The median serum CRP level was comparable in CPPD and OA. The CRP level >5 mg/L was detected in 8 patients with CPPD and in 3 patients with OA (p=0.09). Initial signs of atherosclerosis were present in 11 (42%) patients with CPPD and in 8 (31%) patients with OA (p=0.39). In CPPD, an increase in IMT was associated with a CRP level of ≥5 mg/L in 19% of cases, and in OA – in 12.5% (p=0.08). An increase in IMT >1.3 mm was not found in patients of both groups.
Conclusion. In patients with CPPD and OA, subclinical atherosclerosis is often present according to the CA ultrasound. Early detection of uncomplicated subclinical atherosclerosis in CPPD and OA is necessary for timely initiation of treatment aimed to prevent the progression of atherosclerosis and the development of cardiovascular diseases.

Systemic sclerosis (SSc) can lead to pathological changes in the maxillofacial region, contributing to the violation of the microbiocenosis of the oral cavity with a predominance of pathogenic microflora.
Objective: to study the composition of the oral microflora in patients with SSc. Patients and methods. The composition of the oral microflora was studied in 50 patients with SSc. The control group consisted of 50 subjects without rheumatic diseases. To assess the intensity of dental caries and the level of oral hygiene we used dental indices: the index of caries intensity (Decayed, Missing, and Filled Teeth (DMFT) and the hygienic index (OHI-S).
Results and discussion. Microbiological examination in patients with SSc revealed pathogenic Staphylococcus aureus and Candida albicans > 10-6 CFU in equal percentage of cases (18.9%), which was significantly more frequent than in the control group (p=0.049). In the oral cavity in SSc, there were no representatives of normal microflora (lactobacilli). In patients with SSc, the DMFT index was 17.8±7.1 on average, and OHI-S – 2.3±0.7, which corresponds to a very high level of caries intensity and low indicators of oral hygiene, respectively. When analyzing the microflora of the oral cavity in 90% of cases, a dysbiotic shift of the 3rd degree was stated.
Conclusion. It can hypothesized that the qualitative and quantitative composition of the microflora of the oral cavity affects the development and severity of inflammatory and destructive pathology of the periodontal and oral mucosa. It is necessary to develop and implement an adapted personal hygiene regimen, including cleansing of the tongue and administration of local probiotics, which, as part of complex therapy, can improve the results of SSc treatment.

Objective: to present our own experience of tumor necrosis factor α (TNFα) inhibitors (iTNFα) usage during pregnancy in women with ankylosing spondylitis (AS), to assess AS activity and outcomes of gestation.
Patients and methods. A prospective observation of 55 pregnant women with AS who met the modified New York criteria of 1984. Fifty-six pregnancies were followed. The average age of the patients was 31.7±4.7 years, the duration of the disease was 132.2±85.4 months. The median BASDAI for pregnancy trimesters was 2.4 [1.2; 4.4], 2.7 [1.4; 4.2] and 2.2 [1.5; 4.0], respectively. 14 women received iTNFα 3 months before pregnancy.
Results and discussion. In the first trimester, TNFα was used in 9 (16.1%) patients, in the second – in 9 (16.1%) and in the third – in 5 (9.3%); the median BASDAI for trimesters was 2.3 [1.0; 3.7], 3.4 [1.2; 3.5], 3.0 [0.8; 3.4], respectively. All patients who discontinued iTNFα just before or in early pregnancy had indications for resuming therapy in the second half of gestation. Cancellation of iTNFα at the end of the second trimester was not a risk factor for high activity in the third trimester. There was 1 adverse pregnancy outcome. In other cases, childbirth occurred at 38.9±1.4 weeks, newborns' body weight was 3273.1±435.6 g.
Conclusion. Women with AS who plan a pregnancy should be prescribed drugs with the maximum allowed duration of use during gestation. Cancellation of iTNFα before and in early pregnancy is a risk factor for high AS activity, while renewal of iTNFα therapy during pregnancy is not always effective.

Objective: comparison of the accuracy of risk assessment of low-energy fractures in patients with rheumatoid arthritis (RA) using the prognostic model developed at V.A. Nasonova Research Institute of Rheumatology, and the Russian model of the FRAX algorithm.
Patients and methods. A prospective long-term observational non-interventional study included 70 women aged 40–80 years with a definite diagnosis of RA (ACR, 1987). All patients underwent dual-energy X-ray absorptiometry at baseline and over time; clinical and anamnestic data were analyzed, including information on fractures that occurred during the observation period, confirmed by medical documents.
Results and discussion. The sensitivity and specificity of the FRAX algorithm were 67 and 56%, the sensitivity and specificity of the prognostic model of V.A. Nasonova Research Institute of Rheumatology – 78 and 56%, respectively. The diagnostic accuracy of the FRAX algorithm and the predictive model was 58 and 61%, respectively.
Conclusion. The predictive model developed at V.A. Nasonova Research Institute of Rheumatology, showed higher diagnostic accuracy and sensitivity, as well as comparable specificity with the FRAX algorithm in assessing fractures in RA patients.

Knee osteoarthritis (kOA) is a common cause of turning for medical advice, associated with chronic pain and disability. One of the methods of OA treatment is the local administration of hyaluronic acid (HA) drugs.
Objective: to evaluate the effectiveness of intra-articular (IA) administration of highly purified HA (Armaviskon Plus) in kOA.
Patients and methods. The study group consisted of 58 patients (74.1% women and 25.9% men, aged 59.5±11.8 years) with kOA, experiencing moderate/severe pain (≥40 mm on a visual analogue scale, VAS). All patients received IA injection of HA Armaviskon Plus (2 ml of a 1.5% solution), 2 injections with an interval of 7 days. The effectiveness criterion was the dynamics of pain at rest and during movement (VAS 0-100 mm) and the function of the knee joint according to a numerical rating scale (NRS 0-100 points) 2 weeks, 1 and 3 months after administration of therapy.
Results and discussion. During the treatment, there was a significant improvement in all indicators. The average severity of pain during movement at baseline, after 2 weeks, 1 and 3 months was 50 [40; 60], 30 [20; 40], 15 [0; 30], 20 [0; 30] mm (p<0.001), at rest 20 [10; 40], 5 [0; 20], 0 [0; 20], 10 [0; 20] mm (p<0.05) by VAS. The average values of functional indicators were 40 [10; 60], 10 [0; 40], 20 [0; 40], 10 [10; 30] scores according to the NRS. A decrease in non-steroidal anti-inflammatory drugs demand was recorded: 67.1% of patients were initially taking them, after 3 months – 36.1% (p<0.001). No serious adverse reactions were noted.
Conclusion. IA administration of HA is an effective and safe method for the treatment of kOA. Armaviskon Plus, a highly purified high-molecular- weight HA drug, has shown good results in pain reduction and improvement of function in knee OA as well as a favorable safety profile, which makes it possible to recommend its use in real clinical practice.

Objective: assessment of safety and tolerability of a new generic drug of zoledronic acid (Osteostatics) in patients.

Patients and methods. Clinical observation included 30 postmenopausal women aged 45 years and older (mean age 64±8 years). To determine the safety of the drug of zoledronic acid, all patients underwent biochemical blood test; to assess the tolerability, adverse effects (AE) associated with the administration of the drug were recorded. Fractures that may have occurred during follow-up were also required to be recorded as AE.

Results and discussion. AE was reported by 15 (50.0%) patients. In 13 (43.3%) of them flu-like syndrome (FLS) was noted, including 12 with an increase in body temperature on average to 38.4 [38.0; 38.6] ° C, in 1 (7.7%) – with abdominal pain and nausea, 5 (38.5%) women noted myalgia and/or arthralgia, and 2 (15.4%) – redness and pain in the eyes. In patients who had not previously received bisphosphonate (BP) therapy, AEs were recorded in 62.5% of cases, and in those who had already received such treatment in 15.4%. In most cases, AEs occurred in the first 48 hours, and their duration averaged 2 days.
Conclusion. The incidence of AE was 50.0%, which did not exceed that when using the original zoledronic acid in real clinical practice. The majority of AEs occurred in “naive” patients, developed in the first 2 days after drug administration, and resolved on average within the next 2 days.

Modern therapy of osteoarthritis (OA) consists of four sequential stages and includes non-pharmacological, pharmacological and surgical methods of treatment, and also assumes the possibility of collaborative management of the patient by doctors of different specialties, which allows to optimize the processes of diagnosis and treatment. The article presents simple and convenient algorithms, including diagnostic criteria, options for providing medical care, as well as situations (so-called red flags) that require referral of a patient to a specialist, primarily a rheumatologist. It has been demonstrated that the early use of the well-proven SYSADOA in any localization of OA, in particular the combined drugs of chondroitin sulfate and glucosamine, can increase the effectiveness of treatment, reduce possible functional disorders, and minimize the adverse effects of analgesic therapy.

The article describes the clinical observation of the onset of polyarthritis after COVID-19. Clinical data, laboratory tests' and instrumental methods results in dynamics, as well as approaches to therapy are presented. The discussion reflects modern views on the causes of the development of articular syndrome after SARS-CoV-2, with special attention to the need for a careful study of the history, clinical and laboratory data of patients with COVID-19.

The article discusses the difficulties of differential diagnosis of early arthritis and inflammatory bowel diseases with a predominant clinical picture of extraintestinal manifestations, in particular, articular syndrome. The clinical observation demonstrates features of the course of such conditions, a long diagnostic search and a wide list of diseases included in differential diagnostics range.

Calcium pyrophosphate deposition disease (CPPD) is characterized by polymorphism of clinical manifestations: from asymptomatic course to severe chronic arthropathy with destruction of bone structures. It is believed that calcium pyrophosphate crystals are more often found in the knee and so-called root joints (hip and shoulder), as well as in the triangular fibro-cartilaginous complex. However, CPPD can also affect the axial skeleton. A pathological process localized in the spine is more common in older people and is rare at a young age. The article presents a case of chondrocalcinosis of the cervical spine in a 62-year-old female patient who did not have risk factors.

The article presents an analysis of literature on the efficacy and safety of a new biologic disease modifying antirheumatic drug usage, the interleukin 23 inhibitor – guselkumab (GUS) – in the treatment of patients with psoriatic arthritis (PsA). Two own clinical observations of GUS therapy are described. It has been demonstrated that in PsA of moderate activity and in severe to moderate psoriasis with nail damage, the use of GUS (100 mg at weeks 0 and 4, and then every 8 weeks), allows to achieve remission of peripheral arthritis, enthesitis and psoriasis by the 20th week of treatment as in the monotherapy regimen and in combination with methotrexate. When GUS is re-prescribed (re-treat) after a long break (10 months), its effectiveness is quickly and completely restored. The safety of GUS was confirmed in patients with comorbid pathology, in particular, Gilbert's syndrome, hyperuricemia, metabolic disorders (abdominal obesity).

Antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases. In recent years, APS has been considered as an autoimmune thrombo-inflammatory disease. It has been established that clinical manifestations of APS can persist, progress over time, or debut during an adequate anticoagulant therapy and, in some cases, require administration of immunosuppressive drugs, which indicates the role of autoimmune inflammation in their development. The formation of extracellular neutrophil traps (neutrophil extracellular traps, NETs) is one of the connecting links of inflammation and thrombosis. Netosis is the process by which activated neutrophils in the extracellular space form netlike structures (NETs). This review examines the role of neutrophils and netosis in the pathogenesis of APS and SLE.

The article presents a review of cross-sectional studies and long-term prospective observations dedicated to changes in bone mineral density (BMD) in patients with rheumatoid arthritis (RA) and factors influencing it. The relationship between local bone loss (erosion count) and generalized BMD loss was noted. It is indicated that existing RA treatment strategies are aimed at suppressing inflammation rather than preventing bone resorption. There is evidence that anti-inflammatory therapy using glucocorticoids, methotrexate, and biologic DMARDs in combination with antiresorptive drugs (bisphosphonates and denosumab) helps prevent BMD loss and the progression of erosions. It is emphasized that osteoporosis in RA, which belongs to the immune-mediated secondary osteopathies, is one of the most frequent and serious complications of RA, which determine the unfavorable course and prognosis of the underlying disease.

The article presents an analysis of modern data on the antinociceptive effectiveness of botulinum toxin type A (BTA) in rheumatic diseases (RD). The prospects for the use of BTA in the treatment of pain in different RDs are discussed. We searched for publications in the Medline, Pubmed, Cochrane Library databases. Analysis of literature data has shown that BTA can become an additional method of pain management in many RDs.

The pharmacoinformation approach to the assessment and modeling of drugs involves the use of modern methods of data mining. These methods include: 1) analysis of big data (selection of texts of scientific publications, search for new biomarkers); 2) computer analysis of texts (automatic classification of texts by content, identification of pseudoscientific texts); 3) analysis of metric maps (visualization and analysis of complex patterns, including clustering) and 4) chemoinformation analysis, including the assessment of the effect of drugs on the transcriptome, proteome and microbiome of a person. The article provides examples of the application of these methods of pharmacoinformatics to chondroprotectors containing standardized forms of chondroitin sulfate and glucosamine sulfate.

A fundamentally important task of modern pharmacotherapy of immunoinflammatory diseases (IID) is a significant improvement in the quality of life (QOL) of patients, the fastest and most complete elimination of the most unpleasant manifestations of the disease, restoration of function and working capacity. Specialists in the therapy of various IID took part in panel dedicated to the discussion of this problem: Professor E.L. Nasonov, PhD., member of the Academy of Science; Professor A.M. Lila, PhD; V.N. Amirjanova, PhD; A.E. Karateev, PhD; T.V. Korotaeva, PhD; O.V. Knyazev, PhD; T.A. Lisitsyna, PhD; M.M Hobeish, PhD; E.S. Filatova. PhD.
One of the central issues was the discussion of the need to use the patient's reported outcomes (PROs) indicator in analyzing the results of IID therapy (rheumatoid arthritis, psoriatic arthritis, psoriasis and inflammatory bowel disease). The need for its use is due to the fact that the principal goal of treatment with modern disease modifying antirheumatic drugs (DMARDs) is not only to achieve low activity or remission of IID, but also to maximize the general condition and QOL of patients. Therefore, such manifestations of IID as pain, fatigue, dysfunction, depression and anxiety, etc., must be analyzed in the course of treatment. The development of these symptoms is determined by the main immunopathological process and is associated, among others, with systemic overproduction of a number of pro-inflammatory cytokines. Modern DMARDs: Janus kinase (JAK) inhibitors, in particular tofacitinib, are capable of directly blocking the effect of cytokines on cells (suppressing the intracellular JAK / STAT signaling pathway), quickly and effectively eliminating pain, fatigue and dysfunction. The use of JAK inhibitors seems to be especially appropriate in patients with IID with high inflammatory activity and severe clinical manifestations.