The paper deals with the mechanisms of a T-cell immune response, which depends on the balance between costimulatory and coinhibitory signals that have been called as immune checkpoints (ICP). The imbalance of T-cell activation within ICTs (CTLA4/CD28 and PD1/PD1L) is considered to be a fundamental mechanism not only of autoimmune disease, but also impaired antitumor immunity underlying the development of malignant tumors. The use of monoclonal antibodies against negative regulatory ICTs (CTLA4, PD1, and PD1L) is a major achievement in the treatment of malignant neoplasms in the early 21st century. However, since CTLA4 and PD1 control the activation of auto-reactive T cells, the inhibition of these ICTs is associated with the development of autoimmune disease that is defined as immune-mediated adverse even. The paper considers the clinical manifestations of IMAR, primarily rheumatic ones and discusses the prospects of pharmacotherapy from the standpoint of achievements of modern rheumatology.

The paper gives the definition of remission in axial spondyloarthritides (axSpA), which has been developed by the Spondyloarthritis Study Group of Experts. The work used the Delphi technique. At stage 1, based on the analysis of the data available in the literature and on their own clinical experiences, the experts proposed some variants of the definition of remission and ways of its evaluation in patients with axSpA. At Stage 2, the definitions that had received at least 80% of the votes via anonymous voting were selected and adopted without further discussion. Those that had received an equal number of votes were reconsidered and additionally discussed; then there was repeat voting, by choosing the final definition. As a result of their discussion, the experts formulated the definitions of clinical laboratory and magnetic resonance imaging (MRI) remissions. They proposed the following remissions in axSpA: drug and drug-free, clinical laboratory, and MRI remissions, as well as a remission in the presence and absence of structural changes in the locomotor system, as evidenced by imaging techniques. Criteria for clinical laboratory remission and basic tools for its evaluation that can be used in real clinical practice and researches have been elaborated.

Objective: to assess trends in the overall and primary incidence of rheumatic diseases (RD) from by visit rates in Russia in 2015–2016.

Material and methods. The incidence rates were analyzed on the basis of the data presented in the reports of the Ministry of Health of Russia on adult mortality rates in 2015 and 2016.

Results and discussion. The analysis of adult morbidity rates associated with musculoskeletal diseases (MSDs) revealed a certain downward trend in Russia over 2015–2016. The total number of registered patients with this pathology in 2016 amounted to 16.6 million people, which were 266 thousand people less than in 2015. The primary incidence of MSDs showed a decline by 55 thousand people in this period. The reports of the Ministry of Health indicate that the entire group of patients with MSDs in the section «Rheumatology» has data on six nosological entities: rheumatoid arthritis (RA), reactive arthropathies (RAP), spondylopathies (SP), systemic connective tissue disease (SCTD), osteoarthritis (OA), and osteoporosis (OP). In the RD group OA accounted for the highest incidence rates (4,350,465 cases in 2015 with some reduction (4,285,464 cases) in 2016). In 2015 and 2016, the incidence of RA was 50,905 and 76,823 cases; that of SP was 110,855 and 115,442 cases; that of RAP was 50,905 and 76,823 cases; that of SCTD was 62,265 and 58,276 cases; that of OP was 155.107 and 155,624 cases, respectively. psoriatic arthritis (PsA) accounted for the lowest incidence rates (18,069 and 19,229 cases). The Russian Federation annually registers more than 600 primary cases of OA per 100,000 adult population; less frequent were RA (27.2), SP (18.2), OP (10.2), and RAP (13.5); SCTD and PsA were much less diagnosed (5.9 and 2.84, respectively). Noteworthy are significant variations in the overall and primary incidence in both federal districts and one federal district, making it difficult to attribute only to climatic and geographical factors. This is most likely to be associated with a shortage of trained rheumatologists in individual subjects of the Russian Federation. In addition, it is necessary to monitor the correctness of the diagnosis and its encoding in accordance with ICD-10. 

Glycosaminoglycan-peptide complex (GPC) (Rumalon®) is an injectable slow-release anti-inflammatory agent (SRIA) that has complex anti-inflammatory and metabolic effects. GPC has been successfully used in the treatment of osteoarthritis (OA) for several decades. The agent now returns again to Russian clinical practice. 

Objective: to evaluate the efficacy and tolerability of GPC in patients with knee OA, in whom other SRIAs have been previously ineffective.

Subjects and methods. A study group consisted of 104 patients (92.3% women) (mean age, 63.2±8.5 years; body mass index (BMI), 28.5±5.4 kg/m2) with severe joint pain (≥40 mm on a 100-mm visual analogue scale (VAS)) and/or the need to regularly use nonsteroidal anti-inflammatory drugs (NSAIDs). All the patients received oral SRIAs in the last 6 months and had no improvement. At baseline, VAS pain intensity was 59.4±13.1 mm; the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain was 227.3±90.8; WOMAC stiffness, 97.9±42.1; WOMAC function, 769.2±326.1; total WOMAC scores, 1095.1±426.6. GPC was used by the standard scheme: 25 intramuscular injections every other day per treatment cycle; the results of treatment were assessed at 8 and 12 weeks by VAS and WOMAC pain scores, needs for NSAIDs, satisfaction with treatment (measured on a 1- to 5-pont scale where 1 = no improvement or deterioration and 5 = the best result).

Results and discussion. At 8 and 12 weeks, VAS pain scores decreased by 30.1±18.3% and 36.9±16.9%, respectively; the reductions in WOMAC pain scores were 29.8±16.3 and 38.2±23.4%; WOMAC stiffness scores, 29.2±15.4 and 31.6±17.4%; WOMAC function scores, 27.7±14.7 and 30.6±18.4%; and total WOMAC scores, 27.2±13.5 and 33.6±18.0%. The changes in pain intensity and WOMAC scores were statistically significant in both followup periods (p<0.001). The majority of patients rated their treatment result as good or excellent: 70.2% at 8 weeks and 75.9% at 12 weeks. 31.7% of the patients completely stopped taking NSAIDs at 12 weeks. Two patients were noted to have adverse reactions (pain at the injection site and allergic skin reaction) that did not require treatment discontinuation and completely resolved without consequences after completion of a GPC treatment cycle. Conclusion. GPC is an effective and safe agent for the treatment for OA, as well as in patients with severe OA and inefficiency of oral SRIAs. 

Rheumatoid arthritis (RA) is a multifactorial disease, in which the interaction of the genetic component and environmental factors, determines not only the development of the disease, but also its pronounced clinical polymorphism. We assume that the high inflammatory activity of RA may be determined by the genes, the products of which trigger inflammatory processes.

Objective: to investigate allele and genotype distribution of gene polymorphic variants in active anti-cyclic citrullinated peptide (aCCP)-positive patients with RA from the REMARCA program versus a control group of healthy blood donors.

Subjects and methods. A molecular genetic study enrolled 146 aCCP-positive patients from the REMARCA program and a control group of 314 healthy blood donors without autoimmune diseases and their presence in the history, who were matched with the study group for gender and sex. The polymorphic variants of the genes PTPN22 (+1858C>T, rs2476601), TNFAIP3 (rs6920220, rs10499194), CTLA4 (+49A>G, rs231775), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -892 C>T, rs1800871, -1082 A>G, rs1800896), and MCP1/CCL2 (+2518A>G, rs1024611) were genotyped by a real-time polymerase chain reaction assay.

Results and discussion. The genotype and allele frequencies of polymorphic variants of the genes CTLA4 (+49A>G), IL-6R (+358A>C), and IL10 (592A>C) in the RA group significantly differed from those in the control group. When comparing with the control group, the minor alleles of the CTLA4 and IL10 genes were markers for the risk of aCCP-positive RA with a high inflammatory activity (OR=1.4 [1.1; 1.9], p=0.02 and OR=1.9 [1.4; 2.5]; p=0.0001, respectively). At the same time, the minor C allele of the IL6R gene served as a marker of protection (OR=0.7 [0.5; 0.9]; p=0.03). Logistic regression analysis revealed that there was a statistically significant correlation of the high inflammatory activity indices SDAI, CDAI, and DAS28 with the minor homozygous GG genotype of the CTLA4 gene (OR=2.5 [1.1; 6.0]; p=0.03, OR=2.6 [1.1–6.4], p=0.03 and OR=3.4 [1.3–8.8]; p=0.01, respectively). In addition, the inflammatory activity indices SDAI and CDAI rather than DAS28-ESR were associated with at least one minor A allele (the AA/AC genotypes) of the IL10 gene (OR=2.4 [1.2; 5.1], p=0.02 and OR=2.2 [1.1; 4.7]; p=0.03, respectively). The levels of ESR and CRP were not associated with the examined polymorphisms.

Conclusion. The findings may suggest that there is a relationship of the polymorphisms of the genes CTLA4 (+49A>G, rs231775), IL6R (+358A>C, rs8192284), and IL10 (-592A>C, rs1800872) to high inflammatory activity in the group of aCCP-positive patients from the REMARCA study. 

Objective: to investigate the extent of axial skeleton lesion in a Russian cohort of patients with early peripheral psoriatic arthritis (epPsA).

Subjects and methods. Examinations were made in 89 patients (42 men and 47 women) (mean age, 36.5±10.9 years) with epPsA (duration, 12.1±10.1 months), the diagnosis of which met the CASPAR criteria. In addition to the standard examination, all the patients underwent evaluation of inflammatory back pain (IBP) (ASAS criteria), pelvic radiography, and determination of HLA-B27; 79 patients had additionally magnetic resonance imaging (MRI) of the sacroiliac joints (AIJ). Active sacroiliitis (SI) detected on MRI (MRI SI) was defined as bone marrow edema (osteitis) on T2 STIR. SI on radiography (rSI) was recorded if there were changes in at least one AIJ of Kellgren grade 2 or higher; radiologically significant SI (rsSI) was diagnosed when there were changes in the AIJ, which corresponded to its lesion in ankylosing spondylitis (grade II and higher bilateral SI or grade III and higher unilateral SI). The results of radiography and MRI were assessed by an independent radiologist. The disease activity in patients with IBP was evaluated by BASDAI.

Results and discussion. IBP was identified in 58 (65.1%) patients; it was episodic in 35 (60.3%) and permanent in 23 (39.7%) cases. There was MRI SI in 28 (35.4%) of the 79 patients, rSI in 42 (47.2%), rsSI in 27 (30.3%) cases. 34 (38.1%) of the 84 patients were HLA-B27 positive. The mean BASDAI value was 4.5±1.6. An association was found between the presence of MRI SI and IBP: IBP was present in 92.9% of the patients with MRI SI and in 54.9% of those without MRI SI (p=0.0002). There is a relationship of MRI SI to permanent IBP (p=0.003). An association was found between the presence of rSI and IBP (p=0.047), between rSI and permanent IBP (p=0.01) and between rsSI and IBP (p=0.01). At the same time, SI was asymptomatic in 23.8% of the patients: rSI developed without previous IBP. No association was found between MRI SI/rSI/rsSI and HLA-B27. There was an association between MRI SI and higher peripheral arthritis activity by the DAS28. The mean DAS28 value was 9.34±1.79 in patients with MRI SI and 8.57±1.63 in those without MRI SI (r=0.25; p=0.028). There was an association between the presence of MRI SI and the values of disease activity assessment by a patient (r=0.23; p=0.047) and those of pain assessment by a patient (r=0.31; p=0.0074). An association was found between MRI SI and the affected area of the skin.

Conclusion. In epPsA, there is IBP in 65% of the patients (it was episodic in 60% of them), MRI SI in 35%, rSI in 47.2%, and rsSI in 30.3%. There is an association between IBP and SI detected by any of the imaging techniques (MRI and radiography). In 24% of patients, rSI developed without previous IBP, suggesting that there is latent axial lesion. MRI SI is more frequently detected in patients having higher arthritis activity by the DAS28, higher overall disease and pain assessments by the patient, and a large area of skin lesions. 

Objective: to evaluate the effect of golimumab (GLM) on arterial stiffness in patients with different clinical and immunological subtypes of rheumatoid arthritis (RA).

Material and methods. Examinations were made in 48 patients with RA meeting the 1987 ACR/2010 EULAR classification criteria. The investigators visualized carotid arteries with determination of local vessel wall stiffness and studied regional arterial stiffness with assessment of contour pulse wave analysis before and 52 weeks after initiation of therapy.

Results and discussion. Young and middle-aged RA patients without any concomitant cardiovascular diseases were found to have subclinical great artery involvement that was characterized by increases in intima-media thickness (IMT) and stiffness index β of the common carotid artery (CCA); by rises in peripheral augmentation index (AIp), stiffness index (SI), and reflection index (RI), the intensity of a change in which was associated with high DAS28 and seropositivity for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (antiCCP) antibodies. GLM treatment in patients with RA was accompanied by a statistically significant decrease in DAS28 and a reduction in CCA IMT and local (carotid) stiffness of the vascular bed. More significant correction of the investigated parameters was achieved in patients with the seronegative subtype of the disease; in this group of patients, CCA IMT decreased by 29% by the end of observation (p=0.01), CCA SI β reduced by an average of 28.7% (p=0.0001). At 52 weeks after GLM therapy initiation, contour pulse wave analysis indicated that this subgroup of patients was observed to have decreases in AIp, SI, and RI to the control level; in RA seropositive for RF and/or anti-CCP, they reduced by an average of 1.8 (p=0.0001), 1.2 (p=0.005) and 1.6 (p=0.001) times, respectively.

Conclusion. Along with high anti-inflammatory activity, GLM therapy in patients with RA has a vasoprotective effect on the walls of large elastic-type vessels (decreases in CCA IMT and SI β, AIp, and SI) and small muscular-type arteries (a reduction in RI). 

Objective: to analyze the dynamics of quality of life (QOL) in patients with prior osteoporotic vertebral compression fracture during an 18-month follow-up study.

Subjects and methods. The investigation enrolled 219 patients (mean age, 67.6 years) with vertebral fracture from seven centers of the Russian Federation. QOL was assessed four times using the EQ-5D (EuroQoL-5D) and TTO (Time Trade-Off) questionnaires during an 18-month prospective follow-up study. The work was done within the framework of the International Multicenter Study ICUROS (The International Costs and Utilities Related to Osteoporotic Fractures Study) organized by the International Osteoporosis Foundation (www.icuros.org).

Results and discussion. The patients with vertebral compression fracture showed a statistically significant decrease in QOL throughout the follow-up period. Immediately after the fracture, there was a dramatic decrease in the total EQ-5D score, followed by its gradual increase. However, the emerging trend in QOL recovery proved to be unstable, and by the end of the 18th month, it was significantly lower than that before the fracture. On the contrary, the TTO questionnaire showed that QOL drastically decreased immediately after fracture, but at month 4 it reached the level that was before the fracture, and remained stable until the end of the follow-up period.

Conclusion. The performed investigation enabled us to obtain data on QOL using the EQ-5D (QOL assessment from the social point of view) and TTO (individual QOL assessment) in the population of residents of the Russian Federation, in men and women aged 50 years and older with osteoporotic vertebral compression fracture. 

Cardiovascular catastrophes are the most common cause of death in patients with rheumatoid arthritis (RA). At the same time, the mechanism of progression of atherosclerotic lesions in the vascular bed in RA, including genetic factors, remains a matter of debate.

Objective: to analyze the associativity of polymorphism of the NOS3, PPARG γ , PPARGC1А, PPARGC1B and PAI-1 gene with a high/low cardiovascular risk in patients with RA.

Subjects and methods. The investigation enrolled 73 patients with RA. Of them, 67.1% were at high cardiovascular risk. Ultrasonography of the brachiocephalic arteries with determination of intima-media thickness (IMT) was used as a surrogate marker for cardiovascular risk. A comparison was carried out taking into account the relevant standards. The IMT value exceeding the above parameters was regarded as the sign of a high cardiovascular risk. Single nucleotide polymorphisms in the NOS3 (rs2070744), PPARG2 (rs1801282), and PPARGC1A (rs8192678), PPARGC1B (rs7732671), and PAI1 (rs1799889) genes were investigated by a real-time polymerase chain reaction assay using the intercalating dye SYBR Green I according to the instructions of the manufacturer («Litech», Russia).

Results and discussion. The frequencies of the NOS3 -786ТТ genotypes significantly differed in patients at different cardiovascular risks. Complex genotypes, the frequency of which was prevalent in the low cardiovascular risk group, were identified. At the same time, all genotypes contained the homozygous NOS3 -786ТТ genotype and the genes that were able to regulate its expression. The greatest differences between the analyzed groups were present in the complexes of NOS3-786TT:PPARGC1B 203AlaAla and NOS3 -786TT:PPARGC1B 203AlaAla:12 PPARG ProPro.

Conclusion. Our analyzed gene polymorphic positions can concurrently affect cardiovascular risk in patients with RA. 

soriatic arthritis (PsA) is a chronic inflammatory disease of the joints, spine and entheses from a group of spondyloarthritis (SpA), which is usually observed in patients with psoriasis (Ps). The diagnosis of PsA is based on the CASPAR criteria for psoriatic arthritis. The disease results from interactions between genetic, immunological and environmental factors. The main clinical manifestations of PsA include peripheral arthritis, enthesitis, dactylitis, and spondylitis. PsA must be differentiated from rheumatoid arthritis, gout, reactive arthritis, osteoarthritis, and ankylosing spondylitis. Due to the fact that PsA is a clinically heterogeneous disease, its activity is assessed using complex indices, by taking into account that the patient has arthritis, enthesitis, dactylitis, and spondylitis. The goal of treatment for PsA is to achieve remission or minimal activity of the main clinical manifestations of the disease, to slow down or prevent radiographic progression, to increase life expectancy and quality of life in the patients, and to reduce the risk of comorbidities, which is achieved through a wide range of drugs of different classes. Therapy should be chosen based on the clinical manifestations of PsA and comorbidities in the patients. 

In recent years, there has been a trend toward changing the clinical concept of osteoarthritis (OA). This disease has been considered as an age-related disease and the long-term result of a current pathological process for a very long time. However, many experts are now inclined to consider it necessary to identify the early, pre-X-ray stage of OA, when adequate treatment may not only halt the progression, but also achieve the regression of joint structural changes. This review deals with a number of pathogenetic and clinical aspects of the early stages of OA, which are important for timely diagnosis and pathogenetic therapy choice. It also considers some therapeutic approaches, both a "classic" and recently actively discussed methods for using platelet-rich plasma and autologous chondrocyte transplantation.

Rheumatoid arthritis (RA) is an autoimmune rheumatic disease characterized by chronic erosive arthritis and systemic inflammatory changes, which lead to early disability and worse quality of life in patients. Current imaging techniques have become a new stage of not only in diagnosing, but also in assessing their course and in predicting outcomes. Joint ultrasonography in RA is now considered to be one of the available and widely used techniques. This review of literature provides a detailed analysis of publications on joint ultrasonography in RA. Their results are controversial and frequently cast any doubt on the informative value of this technique. The large number of original publications suggests that rheumatologists are taking a great interest in this method. The review gives the current points of view on the pathogenetic rationale, diagnostic value, and prognostic potential of using ultrasound in patients with RA. It discusses the issues of a methodology for diagnostic procedures, the need of using power Doppler imaging, and current semiquantitative inflammation rating scales. The review presents the existing guidelines for the use of ultrasound in RA, confirming the importance of this imaging technique. 

The review considers the problem of comorbidity of osteoarthritis (OA) and depression. The latter in OA patients is shown to be commonly a component of the well-known triad of pain – depression – sleep disorders, frequently determining the functional abilities and quality of life. The presence of anxiety and depression may increase the risk for poor outcomes of arthroplasty. Environmental stressors in patients require a biopsychosocial approach, by determining the possibilities of drug and non-drug treatment. However, despite the relatively large number of works dedicated to the problem of depression in patients with OA, there are many unsolved questions regarding both its role in the development of the disease and approaches to therapy.

Guidelines for the management of patients with rheumatoid arthritis (RA) envisage that its therapy should be intensified if it is insufficiently effective; at the same time, reduction of its intensity of treatment may be discussed when the set goal has been successfully achieved. The EULAR guidelines allow for dose reduction and even discontinuation of biological agents (BAs), especially when performing combination therapy with BAs and disease-modifying antirheumatic drugs (DMARDs). However, the strategy for this therapy change has not yet been sufficiently clearly defined. In this review, we would like to raise an issue regarding frank rather than early RA in patients with irreversible changes of the locomotor apparatus, who have received DMARDs and/or BAs for a long time. When remission is achieved, it is more difficult to reduce the dose of the drug or discontinue the latter in these cases than in early RA.

The paper describes a clinical case of severe systemic juvenile idiopathic arthritis (JIA) in a child with an early disease onset, which is resistant to multicomponent therapy (glucocorticoids, methotrexate, the tumor necrosis factor-α inhibitor etanercept), and the successful use of the anti-interleukin 6 receptor monoclonal antibody tocilizumab with the achievement of sustained (30-month) drug remission. The therapy with tocilizumab was accompanied by unpredictable adverse events (chronic osteomyelitis of the clavicle, macrophage activation syndrome) and their timely treatment permitted avoidance of life-threatening consequences. The presented case shows difficulties in the follow-up of patients with systemic JIA in clinical practice, requiring alertness to the risk of infectious complications and development of macrophage activation syndrome.

The paper describes a rare case of thoracic spine involvement in a 28-year-old patient with gout that was manifested by acute neurologic symptoms (lower extremity paresis with pelvic organ dysfunction) and that required emergency surgery. Similar cases that are previously described, including the possible variants of the clinical manifestations, tophus localization, surgical treatment, risk factors for axial tophus formation, are separately discussed.

Pulmonary arterial hypertension (PAH) is a progressive and irreversible disease characterized by a steady increase in pulmonary vascular resistance (PVR) and death. Introduction of current PAH-specific drugs has not solved the problem of follow-up of critical patients with PAH associated with systemic sclerosis (SSc). Clinical trials have shown that 1-, 2- and 3-year survival rates are 77, 46, and 33%, respectively. Arguments in favor of starting triple PAH-specific therapy that substantially improves the prognosis of this critical group of patients are being accumulated. The paper describes Russia’s first clinical case of successful up-front triple combination therapy (iloprost, bosentan and sildenafil) in a 40 year old female with SSc and diagnosed functional class (FC) IV PAH. There were clinical, laboratory, and hemodynamic improvements already at 2 weeks after therapy initiation. Thirty-month therapy resulted in a reversal of FC from IV to II, relieved the signs of right ventricular failure, complete right ventricular reverse remodeling and subnormalization of hemodynamic parameters. Hemodynamic improvement including reductions in right atrial pressure to 4 mm Hg, mean pulmonary arterial pressure to 26 mm Hg, and PVR to 2.2 Wood units and an increase in cardiac output up to 7.4 l/min, despite preserved elevated uric acid levels (432 μmol/l). The intriguing feature of this case is critically low values of % predicted/carbon monoxide lung diffusion capacity, which rose from 17% to only 22%, in the presence of positive changes. This clinical case demonstrates the predictive capabilities of up-front triple combination therapy for severe PAH associated with SSc.

The paper discusses the possible causes of the problems related to pharmacovigilance.

The paper is devoted to the anniversary – the 210th anniversary of the birth of the outstanding scientist and clinician Grigory Ivanovich Sokolsky. G.I. Sokolsky made a huge contribution to the development of rheumatology, internal medicine, pathofisiology, and to the enhancement of disease diagnostic capabilities. He published many works in various branches of medicine. The surprising fact is that the young scientist published one or two large works every year in the second half of the 1830s. The scientist won international recognition for his work “On Rheumatism of Heart Muscle Tissue” (1836) that opened up a new understanding of the pathophysiology of rheumatism, by establishing a relationship of joint injuries to the heart. The clinical introduction and teaching of auscultation and percussion also became G.I. Sokolsky’s priceless merit to Russian medicine.