The article presents information on the current state of the problem of autoinflammatory diseases (AID) in rheumatology, reflects the clinical and demographic, laboratory and molecular genetic characteristics of the main monogenic AID (mAID), the most common in real clinical practice. Approaches to the diagnosis and differential diagnosis of these conditions are presented. The variants of classification and diagnostic criteria of the most studied mAID are discussed. The principles of treatment with an emphasis on the use of targeted therapy with interleukin 1 (IL1) inhibitors are shown. The clinical examples demonstrate the variants of late diagnosis of the mAID in adult patients with the disease onset in childhood. Different variants of multi-organ damage are considered. Effectiveness of therapy with IL1β inhibitor kanakinumab is demonstrated. Even in such cases it provided the possibility of significant symptoms regression and restoration of a satisfactory quality of life.

The article is devoted to the new guidelines of EULAR on the management of patients with Behcet's disease/syndrome (BD), which include 5 principles and 10 specific recommendations for the treatment of various organ lesions. The methodology of their creation, as well as unresolved issues of management of patients with BD, which are planned to be investigated in the future, are considered.

Objective: to study the efficacy and safety of rheumatoid arthritis (RA) treatment with monoclonal antibodies to interleukin 6 receptors (IL6R) – sarilumab (SAR) in combination with methotrexate (MT).

Subjects and methods. The study included adult patients with moderate or severe RA and inadequate effect of MT monotherapy. Patients were randomized in a 1:1:1 ratio to subgroups receiving SAR (at doses of 150 or 200 mg) or placebo (PL) every 2 weeks in combination with a weekly intake of MT for 52 weeks. The primary endpoints of the study included the achievement of ACR20 after 24 weeks, the change of HAQ-DI after 16 weeks and assessment of radiological progression of joint destruction (modified total Sharp score mTSS) after 52 weeks.

Results and discussion. In general, the initial characteristics of patients were similar in all groups. A statistically significant improvement of all three primary endpoints was found in the groups of patients treated with SAR 150 and 200 mg compared to the group of PL. ACR20 response after 24 weeks was achieved in 53.6% (p<0.0005), 65.9 and 19.6% of patients respectively (p<0.0001), the average change in HAQ-DI after 16 weeks was 20.53; 20.55 and 20.29 respectively (p<0.0001); the average change in mTSS after 52 weeks was 0.49; 0.11 and 2.30, respectively (p<0.0001).

Conclusion. Both doses of SAR (150 and 200 mg every 2 weeks) in combination with MT demonstrated sustained clinical efficacy in patients with RA, which was confirmed by a significant improvement in symptomatic, functional and radiographic outcomes. SAR therapy was generally well tolerated. The adverse events observed in this study were consistent with the effects of the IL6 blockade.

Methotrexate (MT) is recognized as the main component of the treat to target strategy in patients with rheumatoid arthritis (RA). Unfortunately, MT therapy is not equally effective in all patients with RA, some of them are resistant to such treatment, and have steady progression of destructive changes of the joints, reducing quality of life and leading to disability.

Objective: examination of genetic predictors of therapeutic efficacy and resistance to MT among single-nucleotide polymorphisms (SNP) of folate cycle genes, in particular polymorphisms of the thymidylate synthase gene TSER 2R/3R and TS 6bp del/ins and their haplotypes.

Subjects and methods. The study included 85 patients with RA, who were prescribed MT at a dose of 10 to 17.5 mg/week as a the «first line» disease-modifying antirheumatic drug. The therapeutic response was evaluated with DAS28 after 6 months of continuous treatment. According to the results of this assessment groups of «respondents» and «non-respondents» to MT were identified. Genetic typing of SNP TSER 2R/3R and TS 6bp del/ins was performed by real-time polymerase chain reaction.

Results and discussion. In RA patients with different efficacy of MT, statistically significant differences in the frequency of alleles and genotypes of polymorphic variants of the gene thymidylate synthase were revealed. Thus, in patients resistant to MT homozygous genotype TS 6bp ins/ins frequency was significantly increased (OR 4,3; 95% CI of 1.58 to 11.7; p=0.003), whereas response to the treatment was associated with occurrence of TS 6bp allele del (HR OF 0.48; 95% CI of 0.23 to 1.0; p=0.049), of TSER 2R/3R (OR 0,32; 95% CI 0,12–0,88; p=0.042) and TS 6bp del/ins (OR 0.23; 95% CI 0.08–0.65; p=0.008) genotypes. We have not established statistically significant differences in the frequency of occurrence of haplotypes of the thymidylate synthase gene in RA patients with different therapeutic efficacy of MT, but we found a tendency to increase of the haplotype TS 3R-6bp del (OR 0.39; 95% CI 0.24–1.09; p=0.081) frequency in the «respondents» to the treatment.

Conclusion. Our results may indicate the relationship of the thymidylate synthase gene single nucleotide polymorphisms with therapeutic response to MT in patients with RA.

Pathological changes of large joints (knee, hip) in osteoarthritis (OA) are accompanied by the development of muscle weakness, decreased proprioception and imbalance.

Objective: assessment of skeletal muscles state in women over 65 years old with OA of large joints and determination of the main factors affecting the risk of sarcopenia.

Subjects and methods. In 159 women with OA (mean age 74±6 years), muscle mass was assessed with the appendicular lean mass index (ALM) using dual-energy X-ray absorptiometry (DXA). Muscle strength was measured by hand dynamometer, muscle function was determined by the results of a brief set of physical activity tests (short physical performance battery – SPP). The quality of life was analyzed by the EQ-5D questionnaire, pain assessment was carried out using a visual analog scale (VAS).

Results and discussion. Patients with sarcopenia were significantly more likely to have lower rates of ALM index (p<0.001), body mass index (p<0.001) and muscle strength (p<0.01). The incidence of sarcopenia increased with age (p<0.01). Muscle function measures are reduced in women with OA, regardless of the presence of sarcopenia. Falls in the previous 12 months before inclusion in the study in patients with sarcopenia were observed significantly more often than without sarcopenia: in 90 and 24.8% of cases (95% CI 78.2–96.7 and 17.0–34.0, respectively p<0.001). Clinically expressed pain in large joints in patients with and without sarcopenia was found with the same frequency. The average value of the EQ-5D index in women with sarcopenia was significantly less than without sarcopenia (0.48±0.22 and 0.74±0.27 respectively), mainly due to a decrease of the usual daily activities (p<0.01). However, in women over 85 years of age, the quality of life was comparable regardless of the presence or absence of sarcopenia.

Objective: to assess bone mineral density (BMD) changes in rheumatoid arthritis (RA) patients with osteoporosis (OP) and in women with postmenopausal OP during therapy with denosumab (DSB) for 1 year

Subjects and methods. 121 women were included: the main group – 69 patients with RA (mean age – 60±7 years), 34 (49.3%) from them received glucocorticoids (GC). Comparison group comprised 52 women with primary OP (mean age – 62±10 years). Measurement of BMD using dual-energy X-ray absorptiometry (DXA) was performed in the lumbar spine (L_I–IV), femoral neck (FN), proximal femur as a whole (PF) and distal forearm (DF). DSB was administered subcutaneously at a dose of 60 mg 1 time in 6 months.

Results and discussion. In patients with RA, the average increase of BMD for 12 months of treatment was: in L_I–IV – 4.6%, in FN-2.8%, in PF-3.0% and in DF-0.7%, and in the comparison group – 5.2; 2.1; 2.9 and 0.9%, respectively. There were no significant differences of BMD changes between the groups. Efficacy of DSB therapy in RA patients with OP did not depend on RA activity, duration of GC therapy and cumulative dose of GC. Adverse events that did not lead to the withdrawal of the drug were noted in 3% of the study participants. There were no fractures during the observation.

Conclusion. The efficacy treatment with DSB for 1 year in RA patients with OP and in women with postmenopausal OP is comparable. The use of GC did not have a negative impact on DSB effect.

Objective: to assess the relationship between hematological manifestations of systemic lupus erythematosus (SLE) in the early stage of the disease and development of other syndromes and symptoms of the disease, as well as the nature and severity of internal organs damage during the subsequent five-year period.

Subjects and methods. The analysis of data of examination of 89 patients with SLE during the five-year period was carried out. The frequency of clinical manifestations of SLE, the level of antinuclear and antiphospholipid antibodies, SLICC/ACR damage index (SDI) depending on the presence of hematological manifestations of SLE in the onset of the disease including leukopenia (LP), thrombocytopenia (TP) and autoimmune hemolytic anemia (AGA) were studied.

Results and discussion. In the onset of SLE LP was observed in 21.3%, TP – in 26.9%, AGA – in 8.9% of patients. The presence of LP was associated with an increase of antibodies to SSA frequency, and TP – with more frequent detection of antibodies to Ro-52, cardiolipin and β-2-glycoprotein (p<0.05). Patients with TP in the onset of SLE compared with patients without hematological manifestations, had an increase (p<0.05) of the cumulative incidence of nephritis (83.3 and 42.9%), central nervous system lesions (70.8 and 26.5%), vasculitis (45.8 and 10.2%) and Libman-Sachs endocarditis (20.8 and 6.1%, respectively), which was accompanied by an increase of SDI values (median was 2.09 [2, 1.82; 2.21] and 1.12 [0.81; 1.32], p<0.05). In patients with LP, the cumulative incidence of pneumonitis and Sjogren's syndrome was increased in the onset of SLE compared with patients without hematological manifestations (15.8 vs 6.1% and 15.7 vs 2.0%, respectively, p<0.05).

Conclusion. Presence of TP in the onset of SLE is a predictor of kidneys, central nervous system, peripheral vessels and heart valves damage during the next 5 years.

Therapeutic control of the methotrexate (MT) polyglutamates (MTPG) level in erythrocytes can be an objective marker of the effective dose of MT prescribed for rheumatoid arthritis (RA).

Objective: to assess the relationship between the level of MTPG in red blood cells and efficacy of the MT dose used by RA patients.

Subjects and methods. The study included 60 patients with RA (44 women and 16 men over 18 years) who met the criteria of the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) 2010 and received MT ≥20 mg/week subcutaneously for ≥12 weeks. The patients were divided into two groups of comparable age, sex, alcohol intake, number of smokers, body mass index (BMI), depending on the presence (group 1; n=30) or absence (group 2; n=30) of the effect of MT, according to the EULAR efficacy criteria (DAS28). The concentration of MTPG (total MTPG and metabolites of MTPG _{1, 2, 3, 4, 5}) was determined in erythrocytes by high-performance liquid chromatography with mass spectrometric detection.

Results and discussion. It was found that the levels of total MTPG and MTPG_{1, 2, 3, 5} in erythrocytes did not differ in groups of responders and nonresponders, and the dose of MT was comparable in both groups. At the same time, the level of MTPG₄ in the first group was significantly higher (26.4±6.1 nmol/l; p=0.023) than in the second one (22.1±6.8 nmol/l). Analysis of the ROC curve showed that the values of MTPG₄ <22.5 nmol/l corresponded to the absence of effect of MT. The area under the curve was 0.672 (95% confidence interval 0.536–0.808 (p=0.022), sensitivity 77%, specificity 53.3%.

Conclusion. For effective treatment of patients with RA MT dose should provide MTPG4 level in red blood cells ≥22.5 nmol/l.

Damage of peripheral joints and spine is a frequent manifestation of spondyloarthritis associated with inflammatory bowel diseases (IBD). One of the most frequent and typical manifestations of axial spondyloarthritis (axSpA) is inflammatory back pain (IBP), which is determined according to the IBP criteria of the International society for the study of spondyloarthritis (The Assessment of SpondyloArthritis international Society – ASAS) 2009. The diagnosis of axSpA is based on the identification of combination of typical changes in the sacroiliac joints (presence of sacroiliitis according to MRI or radiography) with a characteristic clinical picture. However, the diagnostic significance of these criteria and the possibility of use in patients with IBD and chronic back pain have not been studied.

Subjects and methods. The study included 84 patients with IBD and back pain. The mean age of patients was 40.5±11.9 years, the duration of IBD symptoms – 8.11±7.67 years.

Results and discussion. In our study, the sensitivity of the ASAS criteria for IBD was 76.9% and specificity – 67.2%, positive predictive value was 0.51, a negative predictive value – 0.87. The likelihood ratio of a positive result is 2.3, the likelihood ratio of a negative result is 0.3.

Conclusion. The main diagnostic characteristics of ASAS IBD criteria (2009) for patients with IBD were comparable with those in the population of patients with chronic back pain (sensitivity – 79.6% and specificity – 72.4%).

Improved diagnosis and treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) contribute to the remission of the disease and improve the quality of life of patients. In this regard, more and more women with RA and SLE decide to have pregnancy, which makes it actual to study the features of its course and outcomes in these diseases.

Objective: to evaluate maternal pregnancy outcomes in patients with RA and SLE.

Subjects and methods. 76 cases of pregnancy were traced prospectively in 72 patients: 32 pregnancies in 29 patients with RA and 44 pregnancies in 43 patients with SLE.

Results and discussion. 72 of 76 (94.7%) supervised pregnancies ended in childbirth with the birth of a viable baby. There were three cases of pregnancy loss in the second trimester in SLE patients with concomitant antiphospholipid syndrome (AFS) and one case (3.1%) of perinatal infant death (a boy and a girl, monochorionic diamniotic twins with reverse arterial perfusion syndrome) in a patient with seropositive RA. Compared with the all-Russian population, the supervised RA and SLE patients more often had prematurely birth (37.5‰, 18.7% and 22.7%) and caesarean section (CS; in 236.7‰, 50%, and 56.8% respectively). In the SLE group CS was conducted due to the emergency reasons more frequently than in RA, (respectively 47,7% and 25%, relative risk of 1.9 [1; 3.7]; p=0.04). CS at the first birth was performed more often during RA and SLE than before the onset of the disease (p<0.001). Preeclampsia in patients with RA was diagnosed more often than in the population (9.4% and 15.7 per 1000 births, respectively). There was a reverse correlation between the timing of delivery and disease activity according DAS28-CRP in II (r= 0.5; p=0.01) and III (r= 0.6; p=0.0005) trimesters of pregnancy, and in patients with moderate and high activity of RA in the third trimester (n=12) delivery was earlier than in the control group (n=20), remission or low activity of RA (p<0.01). In patients with SLE who had birth prematurely (22.7%), the duration of the disease (p=0.02) and the duration of oral glucocorticoid therapy (p=0.003) were greater compared with SLE patients having term birth (70.5%); the dose of glucocorticoids at the time of conception and delivery did not affect the timing of delivery.

Conclusion. Planning of pregnancy in patients with RA and SLE, monitoring during pregnancy and timely correction of therapy contribute to uncomplicated course of gestation and improve maternal outcomes.

The evolution of axial spondyloarthritis (axSpA) and the transition of its nonradiographic to radiographic stage, when ankylosing spondylitis (AS) can be diagnosed, concern many researchers. To clarify this issue, an active search for predictors of the progression of this disease is underway; special cohort studies are being conducted.

Objective: to analyze two-year changes in the magnetic resonance imaging (MRI) signs of sacroiliac joint (SIJ) inflammation and disease activity in patients with axSpA who form a Moscow CoRSAr cohort (a Cohort of early SpondylArthritis) and the role of these indicators in the progression of sacroiliitis.

Subjects and methods. The investigation enrolled 68 CoRSAr cohort patients followed up for two years. All the patients underwent pelvic radiography and SIJ MRI at inclusion in the cohort and then every year. At inclusion in the cohort, nonradiographic axSpA was present in 28 patients, and AS was in 40. Disease activity was determined by BASDAI and ASDAS-CRP. The progression of sacroiliitis was assessed by the total scores of radiographic sacroiliitis.

Results and discussion. The patients' age at inclusion in the cohort averaged 28.5±5.8 years, with a mean disease duration of 24.1±15.4 months and a male proportion of 51.5%; the HLA-B27-positive patients were 92.6%. At two years, 39% of the patients with nonradiographic axSpA went to the AS group. 24-month sacroiliitis progression was observed in 40% of the patients. Disease activity had little impact on the progression of sacroiliitis.

Conclusion. Over two years, almost 40% of patients with axSpA showed an increase in the radiographic stage of sacroiliitis in the CoRSar cohort; this progression was primarily associated with the foci of osteitis according to MRI and correlated little with the activity of the disease.

Recommendations for the management of patients with systemic lupus erythematosus (SLE) in real clinical practice are presented. They take into account the course, activity, damage, and consider assessment of these parameters with validated indices. The characteristic of therapeutic schemes is given, features of monitoring of patients with SLE are considered.

Chronic pain is one of the main manifestations of immuno-inflammatory rheumatic diseases (IIRD), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), which determines the severity of suffering, reduced quality of life and disability of patients. Unfortunately, the use of synthetic and biological disease modifying antirheumatic drugs, as well as non-steroidal anti-inflammatory drugs does not always provide sufficient control of pain in IIRD, even when it is possible to achieve a significant reduction in inflammatory activity. The reason for this is the complex mechanism of chronic pain. It includes not onlystimulation of pain receptors caused by damage of the elements of the musculoskeletal system, but also a change in the perception of pain associated with the phenomenon of central sensitization (CS). CS is characterized by a significant and persistent increase in the sensitivity of nociceptive neurons to pain and nonpain stimuli. One of the main theories of the CS development consider this phenomenon as an inflammatory reaction of the neuronenvironmentthe activation of astrocytes and microglial cells, local hyperproduction of cytokines, inflammatory mediators and neurotrophic factors. Factors contributing to the development of CS in IIRD are obesity, depression and anxiety, damage of the somatosensory system, insufficient relief of pain in the onset of the disease. Clinical manifestations of CS in IIRD is hyperalgesia, allodinia, «expanded pain» and secondary fibromyalgia. An important role in the development of chronic pain and CS plays the intracellular inflammatory pathway JAK-STAT. Therefore, JAK inhibitors, such as tofacitinib, used in RA and PsA, can also be considered as an effective means of controlling chronic pain in these diseases.

Observational cohort investigations are an effective way to study chronic diseases, including psoriatic arthritis, in clinical practice. One of the tools to support such research is registers that collect data related to various aspects of the disease and pharmacotherapy. This review provides information on the main registers of patients with psoriatic arthritis.

In recent years, the long-term survival of patients with systemic lupus erythematosus (SLE) has increased to more than 90%, but there are still quite a few unresolved problems. Although the main objective of the concept of «Treatment of SLE to target» is «remission of symptoms and absence of organ damage», it was recognized that there is currently no generally accepted definition of remission in SLE. The article discusses different variants of the definition of «remission» in SLE.

In the article the analysis of the literature on the impact of biologics of different groups (inhibitors of tumor necrosis factor α, tocilizumab, abatacept, rituximab and interleukin 1 inhibitors) on the production of insulin by the pancreas, insulin resistance and the risk of development of the 2nd type diabetes in patients with rheumatic diseases.

Objective: to assess the possibility of using varying interval between intravenous infusions of tocilizumab (TCZ) as a tool for choosing the optimal treatment regimen in systemic juvenile arthritis (SJA).

Subjects and methods. The observational retrospective study included 72 patients (29 boys and 43 girls) with a SJA fulfilled ILAR criteria, who received TCZ ≥12 months, in which previous therapy with various anti-rheumatic drugs was ineffective. We studied the changes of the main clinical and laboratory parameters of the SJA activity after correction of the interval between infusions.

Results and discussion. In the studied group median age of onset was 3.8 [2.1; 5.9] years, duration of disease before the appointment of TCZ – 26.5 [9.25; 62.25] months. Therapy is continued by 70 patients, the median duration of therapy is 5.0 [2.75; 6.38] years. The initial interval between TCZ infusions was 2 weeks in 49 (group 1) and 4 weeks in 23 patients (group 2). After 6 months of therapy in group 2, the interval was reduced to 2 weeks in 15 (65.2%) patients due to decreased effectiveness. Prolongation of the period between the introduction of TCZ in patients of group 1 who did not reach the inactive status of the disease in the 1st year of the disease resulted in a significant increase of erythrocyte sedimentation rate, C-reactive protein level and exacerbation of systemic manifestations of SJA (p<0.01) in the absence of statistically significant changes of joint status parameters (p>0.05). 40% of these patients had involvement of «new» joints, including hip joints. «Harbingers» of exacerbation in the period of increasing intervals between infusions were: arthralgia (88%), myalgia (65%), sore throat (30%), dysphoria (50%, more often in preschool children), increase of ferritin level and number of leukocytes. In 90.3% of patients who have reached the inactive status of the disease, it was possible to gradually increase the interval between infusions. In 6 patients, TCZ was canceled by gradually increasing the intervals, in 4 of them, therapy was resumed at an initial interval of 2 weeks after 3, 6, 21 and 22 months, respectively, in two patients, a drug-free remission was maintained during 23 and 20 months. Reduction of intervals to the initial 2 weeks was performed in 13 (18.1%) patients. The development of exacerbations with the need to reduce the interval to the initial one was most often observed at 24–35 months of therapy, which chronologically coincided with the period of active growth. Currently, 15 patients receiving TCZ with an interval of 5–6 weeks, and 40 – with an interval of 4 weeks, 9 patients – 3 weeks, in 6 patients attempt to increase the interval to more than 2–2,5 weeks was unsuccessful.

Conclusion. Experience suggests the need to comply with a two-week interval between infusions of TCZ at the initial stage of therapy in most patients with SJA until the inactive stage of the disease, followed by a smooth individual increase in the interval to 4 weeks (2–3 days under careful medical supervision). Appearance of initial signs of exacerbation, requires to reduce the interval to 2 weeks. Before deciding on the complete withdrawal of TCZ, it is advisable to increase the interval between infusions to 5–6 weeks under careful clinical and laboratory control.

Intra-articular administration of hyaluronic acid (HA) is one of the methods of conservative treatment of knee osteoarthritis (OA). However, the data of its efficacy in the modern literature are contradictory.

Objective: to assess the efficacy of intra-articular administration of HA preparations with different molecular weight in the treatment of patients with knee OA and to study the factors that can influence the effectiveness of such therapy.

Subjects and methods. HA preparations were administered to 60 patients with idiopathic and posttraumatic knee OA. The ratio of women to men was 3:1. The average age was 59.5±13.7 years and body mass index – 30.3±5.8 kg/m². The presence of enthesitis was evaluated prior to treatment by the characteristic clinical picture. The x-ray stage of OA was determined in accordance with the classification of Kellgren–Lawrence. Distribution of of knee joint lesions, relationship of femur and tibia anatomical axes, presence of varus and valgus deformities were also evaluated. The patients were divided into three groups: 18 patients received low-molecular (LM), 19 – medium-molecular (MM) and 23 – high-molecular (HM) HA. To assess the efficacy of the treatment the severity of pain on a visual analog scale (VAS) and the total score of the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire before, 1, 3 and 6 months after treatment were evaluated.

Results and discussion. Enthesitis was detected in 17 (28,3%) patients. Stage I of knee OA was diagnosed in 10 (16.6%), II – in 36 (60%) and III – in 14 (23.3%) patients. Varus deformity was detected in 43 (71.7%) patients, neutral axis of the lower limb - in 14 (23.3%), valgus deformity – in 3 (5%). The most significant decrease in the severity of pain was noted in patients with stage I of knee OA: from 54±17.1 to 10.0±10.0 mm. At stage II, the pain decreased from 59.4±12.6 to 45.5±20.3 mm, and at stage III – from 66.4±13.5 to 60.7±23.3 mm. By the 6th month, the severity of pain in patients with enthesitis was higher, and the values of KOOS total score were worse than in patients without it. At stages II and III of knee OA, the ratio of positive to unsatisfactory results for MM, LM and HM HA was as follows: 2:1, 3:1 and 3.6:1. In the group of patients with excellent results, the value of varus deformation averaged 8.5±1.5°, in patients with a good result – 9.8±2.8°, with a satisfactory result – 11.3±4.5°, and with an unsatisfactory – 11.5±3.2°.

Conclusion. Intra-articular injection of HA is very effective at stage I of knee OA. The expression and duration of this effect are reducedwith decrease of cartilage thickness and increase of knee joint varus deformation (i.e., at the II and III stages of knee OA). The presence of varus deformation does not affect HA efficacy. Three factors are important: the appearance of varus deformation of the lower limb with initially neutral axis; the increase of varus deformation; the value of varus deformation >10°.

The article presents the provisions of the Erice Declaration on the safety of medicines and discusses the need for their transformation into the XXI century.