The World Health Organization assigns cardiovascular diseases, cancers, chronic respiratory diseases, as well as diabetes mellitus and some other nosological entities, including mental and musculoskeletal disorders, to main non-communicable diseases. These are considered to be a major public health challenge of the 21st century. In this case, one patient frequently has a set of several age-related chronic diseases that develop simultaneously or sequentially. The management of these patients requires an integrated approach based on the multimorbid nature of pathology. Unlike the definition of comorbidities, which assumes to identify the underlying and related diseases, the concept of multimorbidity of such gradations fails to provide and interprets a patient's chronic diseases as equivalent.

Objective: to assess the presence and nature of multimorbidity in patients with rheumatoid arthritis (RA) and the impact of multimorbidity on disease activity.

Patients and methods. The investigation enrolled 117 patients (mean age, 54.8+14.8years) with RA according to the 2010 ACR/EULAR criteria, who had been examined and treated at the V.A. Nasonova Research Institute of Rheumatology in 2018—2019. The median disease duration was 5.0 [1.5; 9.5] years; the mean DAS28 score was 5.0+1.3. Documentation and anamnesis data were analyzed with emphasis on associated diseases. The Cumulative Illness Rating Scale (CIRS) was used to assess the profile of multimorbidity.

Results and discussion. The patients with RA had a high index of the spectrum of multimorbidity; comorbidity was detected in 96 (82%) cases. The median number of diseases in one patient was 2 [1; 4], the mean total CIRS score was 6.7+3.3; the median value was 2.5 [1; 6]. The number of comorbidities diagnosed before using the CIRS was significantly fewer (by 48%; p<0.01) than was found in the investigation conducted. Chronic kidney disease that occurred in almost half (42.5%) of cases was most commonly undiagnosed in the cohort under study; on average, every three patients were not found to have signs of metabolic syndrome (hyperglycemia in 29% and obesity in 13.5%) and chronic hypoxia (new-onset anemia verified in 24% of cases). There was a correlation of the quantitative equivalent of multimorbidity with the clinical and laboratory measures of RA activity, including the number of painful joints (r = 0.39; p<0.001), overall patient assessment (r=0.37; p=0.03),physician's global assessment of disease activity (r = 0.37; p < 0.01), DAS28 (r = 0.42; p<0.001), CDAI (r=0.37; p<0.001), SDAI (r=0.34; p< 0.001), HAQ (r=0.34;p<0.001). The total CIRSscore did not differ in patients with early- and advanced- or end-stage RA: 6.6+3.5 and 6.7+3.3, respectively (p=0.9).

Conclusion. A systematic screening of multimorbidity should be carried out in all patients with RA. It is advisable to use the CIRS to estimate the prevalence of multimorbidity and its consequences.

Objective: to clarify the primary incidence of type 2 diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) and to compare the prevalence of traditional risk factors (RFs) in groups of patients with and without carbohydrate metabolic disorders.

Patients and methods. A retrospective analysis was carried out in 158 patients with RA (diagnosed at the age of 45 years and older; the disease duration was more than 12 months). The exclusion criteria were concomitant type 1 DM and type 2 DM that was diagnosed before or at the onset of RA. The patients' median age was 62 [57; 68] years. Most RA patients had moderate (41.8%) and high (39.9%) DAS28. New cases of type 2 DM and the presence of hyperglycemia were recorded at the time of the examination. The traditional RFs of type 2 DM were assessed using the Finnish Diabetes Risk Score (FINDRISC).

Results and discussion. The incidence rates of type 2 DM was 9.3 per 1000 patient-years. The patients with developed type 2 DM versus those without DM had a larger number of RFs according to the the FINDRISC questionnaire (6 [5; 7] and 5 [4; 5]; p<0.01), had more frequently experienced myocardial infarction and undergone surgery for myocardial revascularization (27.3 and 2.7%; p<0.01), taken beta-adrenoblockers (72.7 and 33.3%; p<0.05) and calcium channel blockers (36.4 and 12.2%; p<0.05). Fasting hyperglycemia was detected in 10.1% of RA patients. The patients with hyperglycemia versus those with normal venous blood glucose levels more often had obesity (50.0 and 29.8%) and a history of hyperglycemic episodes (43.8 and 19.1%) and less frequently used glucocorticoids (18.8 and 47.3%; p<0.05 for all cases). Conclusion. The high incidence of type 2 DM in RA was associated with the presence of a set of traditional RFs and previous cardiovascular disease, while fasting hyperglycemia was with individual RFs for carbohydrate metabolic disorders. 

There are few studies of the efficiency of therapy with disease-modifying antirheumatic drugs (DMARDs) and biological agents (BAs) in patients with early rheumatoid arthritis (eRA) as part of a treat-to-target strategy.

Objective: to investigate the effects of DMARDs and BAs used in combination with methotrexate (MTX) on clinical course, quality of life (QoL), and the evolution of articular erosions and synovitis in patients with RA.

Patients and methods. The investigation enrolled 151 patients with eRA. At the first stage, the patients received DMARDs. At the second stage, 101 patients with persistent moderate and high disease activity were prescribed MTX at a dose of 25 mg/week or 20 mg/week in combination with infliximab (INF), or 20 mg/week in combination with rituximab (RTX). At the third stage, 20patients with persistent high disease activity were switched to tocilizumab (TCZ) therapy.

Results and discussion. At 12 months of DMARD therapy, a clinical remission was more often achieved in the MTX group. The use of INF or RTX significantly improved QoL in the patients. That of TCZ as a second- and third-line drug led to a significant decrease in DAS28-CRP.

Conclusion. There were no statistically significant differences between the INF and RTMgroups with respect to the time course of changes in CRP, ESR, circulating immune complexes, and the indicators of X-ray progression, which confirms the possibility of switching from a first-line BA to its subsequent lines with an increasing clinical disease activity. TCZ can be a second- and third-line drug when the effect of therapy with other BAs escapes.

Objective: to assess quality-of-life (QoL) dynamics in patients with rheumatoid arthritis (RA) when initiating therapy with biological agents (BAs) in real clinical practice.

Patients and methods. The investigation enrolled patients with RA from the patient cohort participating in the TERMINAL-II multicenter Russian study, who newly initiated BA therapy. In the self-assessment terminal, the patient completed HAQ, EQ-5D, and RAPID-3 questionnaires. DAS28, SDAI, CDAI, and RAPID-3 were used to determine disease activity. The patient's functional status and QoL were assessed using the HAQ index and the EQ-5D questionnaire, respectively. The efficiency of the therapy was analyzed 6 months after the start of the study according to the standard procedures.

Results and discussion. The investigation enrolled 156 RA patients: 79.6% females; mean age, 45.8±13.2 years; disease duration, 7.6±5.6 years. The patients had high RA activity (a mean DAS28 of 5.2±1.2, a mean SDAI of 39.5±16.4, a mean CDAI of 27.5±10.4, and a mean RAPID-3 of 15.1±3.6) and previous inefficacy of synthetic disease-modifying antirheumatic drugs (DMARDs) after at least 6 months of therapy. Only 1.2% of patients had a good functional status comparable to the population-based control (HAQ 40.5). 70% of patients needed to take non-steroidal anti-inflammatory drugs (NSAIDs). The first BA was chosen in accordance with the recommendations for administration of BAs and in terms of their availability in a specific region of the Russian Federation. The first prescribed BA was tumor necrosis factor-a (TNF-a) inhibitors in 112 (71.8%)patients, anti-B-cell therapy in 14 (9.0%), an interleukin-6 receptor inhibitor in 16 (10.3%), and a leukocyte costimulatory inhibitor in 14 (9.0%). Comparison of the patients receiving newly initiated therapy with TNF-a inhibitors and drugs with other mechanisms of action showed that the patients who had abatacept received higher doses of methotrexate (MTX), but lower doses of glucocorticoids (GCs) than those who were prescribed rituximab and tocilizumab. A statistically significant decrease in DAS28, SDAI, CDAI, and RAPID-3 scores was achieved after 6 months of therapy. Improvements of functional status and QoL in patients were also noted (p<0.0001). The patients continued to receive MTX. During the follow-up period, its dose remained almost unchanged: it averaged 15.7±3.8 and 15.7±3.7 mg/week at the beginning and the end of the study, respectively. Due to decreased inflammation, the dose of CS was reduced (on average, from 5.8±2.5 to 5.1±2.6 mg/day; p=0.02), the number of patients requiring NSAIDs declined (from 72.4 to 63.8%). DAS28, SDAI, and CDAI remission and low disease activity were achieved in 38.1, 16.5, and 20% of patients, respectively. The functional status improved in most patients with RA: 20, 50, and 70% improvements in HAQ were observed in 59.4, 46.9, and 28.7% of cases, respectively. QoL improvements were seen in two thirds of the patients: 30, 50, and 70% improvements in 58.3, 29.5, and in 23.7%. After 6-month follow-up, GC therapy was completely discontinued in 4.6% of patients; their dose was reduced in 5.3%, and 8.6% completely refused to take NSAIDs.

Conclusion. Biologic therapy was shown to be effective in RA patients with an inadequate response to synthetic NSAIDs in real clinical practice. The patients preferred the subcutaneous injection of BAs. Biologic treatment in most patients was initiated with TNF-a inhibitors, mainly with adalimumab. Six-month therapy could reduce disease activity and improve functional status and health-related QoL in two thirds of severe patients.

Rheumatoid arthritis (RA) is one of the most common rheumatic diseases. Dendritic cells (DCs) as the main antigen-presenting cells play an important role in the pathogenesis of RA. There are two major DC populations: myeloid and plasmacytoid DCs (mDCs and pDCs). B cells as antibody-producing cells also play an important role in the pathogenesis of RA. The probability of achieving low disease activity and clinical and laboratory remission has been proven to be maximal in the very early period of the disease and in the patients who have not been previously prescribed disease-modifying antirheumatic drugs (DMARDs). In this connection, it is necessary to elaborate additional criteria and biomarkers for early RA.

Objective: to investigate the subpopulation composition of DCs in patients with early-stage RA.

Patients and methods. The investigation enrolled 60patients with RA who met the 2010 ACR/EULAR and the 1987ACR criteria. The patients with RA were divided into two groups: 1) 30patients with early RA (the disease duration was not more than 1 year); 2) 30 patients with advanced RA. A control group consisted of 30 patients with osteoarthritis (OA) who met the ACR criteria. All the patients with RA were treated with DMARDs. The patients with early RA had not previously received DMARDs; after being included in the study, they were prescribed methotrexate 15-20 mg/week. The patients with advanced RA took methotrexate 15-25 mg/week (n=24), sulfasalazine 2 g/day (n=5), or leflunomide 20 mg/day (n=1).

At the first stage, the levels of different subpopulations of DCs and B lymphocytes were studied in the patients with early RA before initiation of therapy and in those with advanced RA and in the control persons. At the following stage, the time course of changes was investigated in the subpopulation composition of DCs and B lymphocytes during therapy.

Results and discussion. The subpopulations of peripheral blood DCs in early RA were characterized. A subpopulation of mDCs was shown to dominate in the patients with early RA versus those with advanced RA or osteoarthritis (OA). In addition, the patients with RA showed a high B lymphocyte level. It was noted that there was no significant differences in the level of pDCs between RA and OA patients and there was an inverse relationship between the relative peripheral blood level of pDC and disease activity, which confirms the immunosuppressive role of pDCs in the pathogenesis of RA. The levels of mDCs and B lymphocytes during DMARD therapy were ascertained to significantly decrease to those seen in healthy donors.

Conclusion. Thus, the findings suggest that the number of mDCs and B lymphocytes increases in patients with early RA, unlike those with OA. In addition, the change in the number of mDCs and B cells during therapy is associated with the dynamics of disease activity and may suppose that mDCs are a target for the action of DMARDs.

Objective: to evaluate the efficiency and safety of therapy with subcutaneous (SC) methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA) without systemic manifestations.

Patients and methods. The paper presents the results of a prospective study of the efficacy and safety of MTX in 247patients aged 1 to 17 years with articular variants of JIA, as well as the frequency of indications for prescribing biological agents for this category of patients. JIA occurred without systemic manifestations in all the patients, including 106 with oligoarticular articular JIA, 94 with rheumatoid factor (RF)-negative polyarticular JIA, 15 with RF-positive polyarticular JIA, 20 with enthesitis-related JIA, and 12 with psoriatic arthritis. JIA was diagnosed according to the ILAR criteria. After verification of the diagnosis, all the patients were prescribed SC injections of MTX at a dose of 15 mg/m2/week.

Results and discussion. After 3 months of MTX therapy, 50 and 70% improvements according to the ACR pediatric criteria were registered in 65 and 53% of the patients, respectively. After 6, 9, and 12 months of therapy, the stage of inactive disease or remission was observed in 44.5, 85, and 100% of the patients, respectively.

Conclusion. Parenteral MTX administration contributes to the achievement of disease remission and the restoration of joint functions in patients with JIA without extra-articular manifestations. Along with its high therapeutic efficacy, MTX had a good tolerability and a favorable safety profile.

Using of more convenient drug regimens is one of the ways to increase patient adherence to treatment for osteoarthritis (OA).

Objective: to evaluate the efficacy of Alflutop® in an alternating dosing regimen versus its standard administration to patients with knee OA.

Patients and methods. The investigation included 130 randomized patients who had Kellgren—Lawrence Grade II—IIIprimary tibiofemoral knee OA with pain intensity on walking at least 40 mm on a visual analogue scale and needed to take nonsteroidal anti-inflammatory drugs (at least 30 days in the previous 3 months). The patients were divided into two groups: 1) those who received Alflutop® 2 ml intramuscularly (IM) every other day (a total of 10 injections); 2) those who used the drug 1.0 ml IM daily for 20 days. The duration of the investigation was 14 weeks.

Results and discussion. Just on days 20/21 of treatment, the patients of both groups were recorded to have statistically significant reductions in knee pain on walking (p<0.001) and in all WOMAC indices (pain, stiffness, functional failure). There were further reductions in pain and WOMAC within one month or more after completion of therapy (p<0.001), which suggests that the drug has a pronounced after-effect. A statistically significant improvement in quality of life according to the EQ-5D was also noted throughout the study period (p<0.001). The assessment made according to the OMERACT-OARSI criteria was also consistent with the findings. By the end of treatment, its respondents were 84.6 and 81.5% of the patients in Groups 1 and 2, respectively.

Conclusion. The data from this investigation confirm the comparable high efficacy of Alflutop® used in both standard and alternating treatment regimens. During treatment, there was a significant reduction in pain intensity and improvements in knee joint function and quality of life. The investigation has shown that the drug can be used at a dose of 1 ml not daily for 20 days, but also at 2 ml every other day for 10 days.

The paper describes a clinical case of rheumatoid factor-seropositive polyarticular juvenile rheumatoid arthritis (JRA) concurrent with new-onset Sjo gren's syndrome (SS) in a teenage girl. It discusses the clinical features of SS and the problems of its diagnosis in pediatric practice. Erosive arthritis with rapidly progressive joint destruction concurrent with SS that was highly active according to biopsy findings, as well as the nature of the immunological parameters served as the basis for using rituximab (RTM), a chimeric anti-CD20 monoclonal antibody. Although RTM is not registered for use for this disease in childhood, an alternative biological agent was unavailable in this clinical situation. The therapy was observed to be highly effective. Just after the first cycle of RTM therapy, the values of acute-phase markers became normal, arthralgias and exudative joint phenomena diminished, and morning stiffness ceased. Twelve months after therapy initiation, the patient achieved remission of JRA with positive changes confirmed by control sialography and sialometry.

The given clinical example convincingly demonstrates the feasibility of using RTM in patients with JRA concurrent with SS with resistance to therapy with classical immunosuppressive drugs and with the undesirability of using tumor necrosis factor-а inhibitors due to the increased risk of lymphoproliferation in SS.

The paper describes a clinical case of a female patient with systemic lupus erythematosus. The features of this case are lobular panniculitis (Pn) con-current with other typical clinical and laboratory signs of the underlying disease, as well as the absence of the effect of previous therapy. The main directions of the differential diagnosis of idiopathic lobular Pn and lupus Pn that required exclusion of other rheumatic diseases are highlighted.

The paper discusses the results of clinically using the interleukin-1_ inhibitor canakinumab in a patient with chronic tophaceous gout, IgA nephropathy, and chronic kidney disease with resistance to traditional anti-inflammatory drugs (colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and high-dose glucocorticoids) and a history of failed urate-lowering therapy. It demonstrates the possibility of safely using subcutaneous canakinumab 150 mg that is superior to therapy with high-dose prednisone (40-80 mg/day) and NSAIDs. Canakinumab has also reduced the risk of exacerbations of arthritis when choosing urate-lowering therapy.

In real clinical practice, rheumatologists constantly face with the problem of differential diagnosis of rheumatic (RDs) and non-rheumatic diseases, as well as various RDs with similar symptoms. Most of the RDs are multisystemic and heterogeneous in clinical symptoms, course, and outcomes. Their clinical, laboratory, and instrumental signs that could be considered as the gold standard to confirm the diagnosis are not defined in all nosological entities. Therefore, the diagnostic process, especially in early arthritis caused by systemic inflammation, is complex cognitive in nature and requires the synthesis of many data that are usually not taken into account in a simple algorithm, the basis of which is a set of classification criteria.

The review presents the issues of differential diagnosis of early arthritis in gastrointestinal tract diseases, such as celiac disease, microscopic colitis, PPP syndrome, etc.

In 2008, the term cardiorenal syndrome (CRS) was proposed by the Acute Dialysis Quality Initiative (ADQI) Group to denote pathological reciprocal conditions involving the heart and kidneys, which develop due to acute or chronic dysfunction of one of the organs, followed by acute or chronic dysfunction of the other one. The problem of CRS in patients with rheumatoid arthritis (RA) has not been studied. Of the greatest interest is CRS type 5 or secondary CRS that occurs in patients with systemic diseases, including in those with RA. Currently, there is no doubt that the risk of developing cardiovascular diseases in RA patients and the prevalence of non-ischemic and ischemic chronic heart failure (CHF) are higher than those in the general population. There is evidence that the prevalence of chronic kidney disease (CKD) and renal pathology-associated cardiovascular risk factors (RF) is high in patients with RA. In addition to traditional RFs for cardiovascular and kidney diseases, autoimmune inflammation is an independent predictor for CHF and CKD. The characteristics of CRS in RA should be investigated to develop an effective treatment strategy for this category of patients.

The review contains information about the physiology of the hemostatic system and its components and discusses the relationship of the hemostatic system to inflammation. It also describes the physiology of normal hemostasis, the interaction of platelets with endothelial cells and leukocytes, as well as with von Willebrand factor and the complement system and their role in rheumatoid arthritis.

The paper summarizes the data available in the literature and those from the authors' studies on the molecular and cellular mechanisms of apoptosis and their state in rheumatoid arthritis (RA). Impaired apoptotic processes in RA are one of the causes of synovial cell hyperactivation that leads to the increased inflammatory process, synovial hyperplasia, and progression of the disease as a whole. The most important feature of a cellular continuum in the affected synovial fluid is the coexistence of just two mechanisms that control apoptosis: 1) a traditional activation mechanism leading to progressive joint inflammation and destruction and 2) an inhibitory mechanism implemented through the expression of proapoptotic molecules. The apoptotic factors are a useful tool for assessing the prognosis of RA and a promising target for pharmacotherapy.

The problem of infectious comorbidities (ICs) remains relevant in modern rheumatology. This is due to both the presence of an autoimmune rheumatic disease and the need to use immunosuppressant drugs. The paper highlights the current aspects of main ICs (tuberculosis, pneumonia, chronic viral infections) in patients with rheumatoid arthritis (RA). It also shows the importance of measures to prevent ICs in the treatment of RA. Emphasis is placed on the importance of primarily influenza and pneumococcal vaccination in RA patients in order to reduce the incidence of lower respiratory tract infections and the risk of death from these conditions.

Heart failure (HF) is one of the major public health problems in developed countries. Hyperuricemia (HU) is often found in patients with chronic HF (CHF) and is a well-known independent predictor for mortality and re-hospitalization for the progression of HF. The association of HU with worse clinical outcomes in patients with CHF may be attributed to the effects of uric acid (UA) and the enzyme xanthine oxidase (XO) on the vascular endothelium, which leads to the release of inflammatory cytokines and reactive oxygen species. The presence of this mechanism leads to an interest in exploring the potential benefits of inhibiting XO in patients with HF. XO inhibitors are likely to become a new tool to improve prognosis in these patients.

Analgesic therapy is an essential element of combination treatment in patients with rheumatic diseases (RDs). However, pain killers can cause serious complications. This risk is especially great in patients with comorbidities. Therefore, the individual choice of pharmacological agents for controlling acute and chronic pain in a particular patient largely depends on the presence of comorbidity. This review discusses the incidence of comorbidities in different RDs, the characteristics of adverse reactions from the intake of main analgesics, such as paracetamol, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the rational choice of a NSAID in real clinical practice.

Osteoarthritis (OA) and other large joint diseases remain an unsolved problem of modern orthopedics and rheumatology. The use of intra-articular injections of various drugs, including hyaluronic acid, is widespread in both our and foreign countries; however, the efficiency of treatment is not always sufficient, despite its high cost. One of the most effective and inexpensive methods for treating OA is intra-articular ozone therapy that has recently become widespread. The ability of ozone to suppress joint inflammation, to improve blood supply, including that to the subchondral bone, and to reduce pain is considered to be the main advantages of this method. The safety and low risk of adverse reactions allow ozone to be used in a wide range of patients.

Objective: to carry out a statistical analysis of clinical material obtained in an open-label observational study of the efficacy and safety of injectable chondroitin sulfate (ICS) in real clinical practice.

Patients and methods. A total of 170patients with knee osteoarthritis (OA) (78.8% females; mean age, 60.5+8.3 years) who experienced severe pain and needed to regularly take non-steroidal antiinflammatory drugs (NSAIDs) were examined. All the patients received a cycle of therapy with ICS (25 intramuscular injections every other day). The treatment results were assessed by the changes of pain intensity at rest and during movement and general health status (a 100 mm visual analogue scale) at 2 months after therapy initiation. The dynamics of NSAID use, therapy tolerance, and patient assessment of treatment outcomes were also taken into account.

Results and discussion. There were decreases in the median severity of pain at rest from 40.0 [20.0; 70.0] to 10.0 [0.0; 20.0] mm, in pain during movement from 65.0 [58.0; 80.0] to 20.0 [10.0; 30.0] mm, and in overall health status assessment from 60.0 [50.0; 70.0] to 20.0 [10.0; 40.0] mm (p < 0.001). It might be possible to discontinue NSAIDs or to reduce their dose/frequency in 87.9% of patients. 83.3% of patients rated their treatment results as good and excellent. No serious adverse reactions were observed.

Such a beneficial effect of therapy should be taken with some caution, since it has been obtained during an open-label uncontrolled observational study. Although the injection of this type of pharmacological agents is practically not used in Western countries; Russia has meaningful and generally positive experience with injectable slow-acting symptom-modifying drugs (SMDs), including CS. The advantages of this procedure are an enhanced bioavailability of SMDs, an accelerated onset of an analgesic effect, and higher patient adherence to therapy. Conclusion. The findings showed the good efficacy and tolerance of ICS in patients with knee OA in real clinical practice.

Glucosamine is part of the human metabolome required for the biosynthesis of polymer glycosaminoglycans in connective tissue. In addition, the glucosamine molecule itself has anti-inflammatory and regenerative properties. This paper presents the results of a systematic analysis of fundamental and clinical studies, which indicate the anticoagulant and antiaggregatory effects of a highly purified pharmaceutical substance of microcrystalline glucosamine sulfate (mGS). The main molecular mechanisms of its antithrombotic effects are most probably the mGS molecular mimicry of heparan sulfate activity, the activation of CD44 receptor, and the inactivation of the NF-KB signaling pathways in platelets. A quantitative chemoreactome study has shown that the antithrombotic effects of mGS in the human reactome are due to the inhibition of: ’) proper platelet aggregation; 2) platelet adhesion and activation receptors; 3) endogenous synthesis of thromboxanes; 4) coagulation by reducing the activity of coagulation factors.

The paper describes the occurrence of polyarteritis nodosa in a patient with rheumatoid arthritis during treatment with tofacitinib. It considers the reasons why this condition should be regarded as an unforeseen borderline paradoxical adverse reaction.