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The aim – to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler’s syndrome (SchS) according to a multicenter Russian cohort.Materials and methods. In an observational retrospective study for a 10-year period (2012–2022), 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis, among them 8 women, 9 men, were included in the study. The diagnosis of all corresponded to the Strasbourg diagnostic criteria.Results. The age of patients ranged from 25 to 81 years (Me 53 [46; 56] years). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46 [39; 54] years), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5 [3; 6] years), in 3 it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDS (CAPS, TRAPS, HIDS) were excluded from all patients at the prehospital stage. The guiding diagnosis for all was Still’s disease in adults. Clinical manifestations of the disease included: fatigue, lethargy, fatigue, rash and fever in all, skin elements were urticular in all, accompanied by itching in 6 (37.5%). Bone pain had 12 (70.6%), arthralgia – 16 (94.1%), arthritis – 9 (52.9%), myalgia – 7 (41.2%), weight loss in 4 (23.5%). Lymphadenopathy (6), enlarged liver (6), pericarditis (4), angioedema (6), redness and dryness in the eyes (3), sore throat (2), abdominal pain (1), distal polyneuropathy (2), paraesthesia (1), chondritis of the auricles were less common (1). Monoclonal gammopathy was detected in all with a secretion level of 2.9–15.1 g/l: IgMk (n=10 (64.7%)), less often IgMλ (n=2), IgGk (n=2), IgGλ (n=1), IgAλ (n=1). Ben-Jones protein was not detected in any of them. All patients had an increase in the level of ESR, CRP. 16 patients before inclusion in the study received GC (94.1%) with a temporary effect and its escape with dose reduction or cancellation, DMARD – 7, among them methotrexate (5), hydroxychloroquine (2), cyclophosphamide (1), also NSAIDs and antihistamines in all, biological drugs: anti-B-cell the drug rituximab (1), monoclonal AT to IgE – omalizumab in 2 (1 – without effect, 1 – partial effect). 11 patients were prescribed IL-1: canakinumab – 9 (52.9%) subcutaneously once every 8 weeks, anakinra – 4 (23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1, 10 out of 11 (90.9%) received a complete response from the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In 1 patient, a partial response was received to the administration of anakinra, and when switching to canakinumab, the effect of treatment was finally lost. 1 patient received IL-6 for 8 months with incomplete effect and transition to IL-1 with positive dynamics. In 1 patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation, but subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born in the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAE was noted.Conclusion. SchS is a rare multifactorial/non–monogenic AID that needs to be differentiated from a number of rheumatic diseases and other AIDS. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1 is a highly effective and safe option in the treatment of such patients.

Juvenile idiopathic inflammatory myopathies (JIIM) are rare diseases in which the prognosis is largely determined by timely diagnosis, timing of prescription and effectiveness of therapy.Objective: to characterize the clinical phenotypes, the results of paraclinical examination methods, the spectrum of autoantibodies, as well as therapeutic options in patients with JIIM.Patients and methods. The retrospective study included 37 patients with JIIM hospitalized in the pediatric department of the V.A. Nasonova Research Institute of Rheumatology from 2016 to 2020. All patients underwent a standard clinical and laboratory-instrumental examination in accordance with the diagnosis and severity of the condition.Results and discussion. Twenty-three of the 37 JIIM patients had juvenile dermatomyositis (JDM), 1 had polymyositis, and 13 had overlap-myositis (OM). The ratio of boys and girls was 1:1.7. The median age of onset for JDM was 6.9 years, and OM was 11.3 years. All patients had skeletal muscles involvement, dysphagia was detected in 52.2% of cases of JDM and in 15.4% of cases of OM. An increase in the level of creatine phosphokinase at the time of diagnosis was observed in 72.9% of patients, of lactate dehydrogenase – in 81.1%, of alanine aminotransferase - in 67.6%, of aspartate aminotransferase – in 75.7%. Heliotrope rash and/or Gottron's syndrome were observed in 100% of patients with JDM and in 30.8% with OM. Lung involvement was found in 27% of children. The myopathic capillaroscopic changes were present in 95.2% of patients with JDM and 53.8% with OM. Myositis-specific autoantibodies were found in 10.8% of patients with JIIM.All patients received glucocorticoids, 81.0% methotrexate, 18.9% hydroxychloroquine, 8.1% cyclophosphamide, 8.1% cyclosporine, 2.7% mycophenolate mofetil, 2.7% azathioprine, 67.6% - intravenous immunoglobulin. Biologic disease modifying antirheumatic drugs (bDMARDs) were prescribed to 26% of patients with JDM and to all patients with OM (only in 51.3% of cases with JIIM). The median duration of illness before initiation of bDMARDs therapy was 2.25 years. 58.8% of patients were treated with rituximab (RTM), 41.2% with abatacept (ABA). In 1 patient with OM, represented by a combination of systemic lupus erythematosus and JDM, three bDMARDs were used sequentially: ABA, etanercept and RTM. All patients achieved inactive disease status.Conclusion. JDM is the most common phenotype of JIIM, which is characterized by an earlier age of onset, skin involvement that precedes the development of myopathy, and typical capillaroscopic changes. The conclusion was made about the high efficacy and acceptable safety profile of bDMARDs therapy in children with JIIM, with careful monitoring of its tolerability. bDMARDs can be prescribed even in the early stages of the disease in the presence of unfavorable prognostic factors.

Ferritin is a complex protein composite (iron protein) that plays the role of the main intracellular iron depot in humans and animals, consisting of the protein apoferritin and the ferric atom in the composition of phosphate hydroxide. The reference value of ferritin in women is 200 μg/l, in men – 300 μg/l. Ferritin is a marker of total body iron stores, and low levels are specific for iron deficiency. Ferritin is also involved in immune processes and has both pro-inflammatory and immunosuppressive activity. Hyperferritinemia is a nonspecific symptom that occurs in a number of immunoinflammatory, infectious diseases, as well as during body iron stores overload. Hyperferritinemia is a criterion sign of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis, systemic lupus erythematosus and Kawasaki disease, as well as a predictive biomarker of adult-onset Still's disease. High ferritin levels occur in catastrophic antiphospholipid syndrome, as well as in infectious pathologies such as septic shock and COVID-19, including multisystem inflammatory syndrome associated with COVID-19. Ferritin concentration is an important parameter for assessing the activity and prognosis of the disease, which allows a rational approach to the choice of therapy in these patients.

Autoinflammatory diseases (AIDs) are a heterogeneous group of rare genetically determined conditions, the main manifestations of which are episodes of fever in combination with other signs of systemic inflammation: skin rashes, musculoskeletal and neurological disorders, damage to the organs of vision, hearing, etc., as well as acute phase markers and the absence of autoantibodies. The use of biological therapy, especially inhibitors of interleukin 1 (iIL1), in most common monogenic AIDs (mAID) – FMF, TRAPS, HIDS/MKD, CAPS – has shown its high efficiency and led to significant progress in the treatment of these patients. Currently, iIL1 are the first-line drugs for mAIDs therapy, primarily CAPS. In the case of their ineffectiveness or intolerance in certain situations, other biologic disease-modifying antirheumatic drugs can also be used – inhibitors of tumor necrosis factor α and iIL6, but this issue needs further investigation. The article describes a patient with mAID, in whom the diagnosis was made more than 40 years after the onset; administration of targeted therapy even in the late stages of the disease led to a significant improvement in many symptoms and quality of life.

Objective: to assess the frequency of prescription, efficacy and tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) therapy in patients with major monogenic autoinflammatory diseases (mAID) according to the Federal Rheumatology Center clinical practice. Patients and methods. From 2008 to 2020 years, 158 patients with mAID were included in the study, 53 of whom were prescribed bDMARDs: 12 patients had Familial Mediterranean Fever (FMF); 26 – Cryopyrin-Associated Periodic Syndromes (CAPS), including 21 patients with MuckleWells Syndrome (MWS) and 5 – with Chronic Infantile Onset Neurologic Cutaneous Articular / Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID), 12 patients had Tumor necrosis factor (TNF) receptor-Associated Periodic Fever Syndrome (TRAPS) and 3 – Hyper-Immunoglobulinemia D-syndrome (HIDS/MKD). Among all these patients 25 were male and 28 female, aged 1.5 to 44 years, 45 were children (under 18) and 8 adults. Interleukin 1 inhibitors (iIL1) were prescribed in accordance with the following scheme: canakinumab – subcutaneously 2–5 mg/kg or 150 mg per injection, every 4–8 weeks; anakinra – subcutaneously 1–5 mg/kg or 100 mg/day, daily. Etanercept (ETC) was injected subcutaneously 0.4–0.8 mg/kg 1–2 times a week, and adalimumab (ADA) was injected subcutaneously 20–40 mg once every 2 weeks. Tocilizumab (TCZ) was administered intravenously, 8–12 mg/kg once every 2–4 weeks. The duration of the disease at the time of treatment initiation ranged from 1 to 44 years. The duration of bDMARDs therapy in patients with mAID ranged from 1 month to 12 years.Results and discussion. From 158 patients with mAID, in 53 (33.5%) bDMARDs were administered. They were used more often in patients with CAPS (56.6%), and less often – in TRAPS (26.4%), FMF (28.3%) and HIDS/MKD (5.7%). iIL1 were the most frequently prescribed bDMARDs (90.6%): canakinumab (in 38 patients) and anakinra (in 10), they were mainly used in patients with CAPS, in 2/3 of patients with TRAPS, HIDS/MKD and colchicine-resistant FMF. During the first days of iIL1 treatment, all patients with mAID showed a statistically significant clinical improvement: normalization of general condition, emotional recovery, relief of fever, disappearance of rash, decrease in the severity of lymphadenopathy and hepatosplenomegaly, relief or significant positive dynamics of eye symptoms, subjective improvement in hearing and audiogram (with dynamic control in patients with CAPS), decrease in the level of acute phase markers (in all cases). In 7 patients with CAPS, who received anakinra, after a positive response was achieved, switching to canakinumab was performed, which maintained the full effectiveness of therapy. TCZ (in 7 patients) and inhibitors of tumor necrosis factor α (iTNFα) – ADA (in 3) and ETC (in 4), – were used less frequently. iTNFα were more often prescribed to FMF patients with a complete response to treatment. Tolerability of bDMARD therapy was satisfactory in all patients. Conclusion. Currently, iIL1 are the first line of therapy among biological agents for mAID, especially in patients with CAPS. If they are ineffective or intolerant in certain situations, alternative bDMARDs (iTNFα and IL6 inhibitors) can also be used, but this issue needs further study.

The article presents a case of periodic fever (PF) in a 35-year-old patient, who did not have hereditary and proven genetic factors of the disease, which was characterized by an atypical course with variable in duration and frequency severe abdominal pain and febrile fever attacks, increased acute phase reactants and ineffectiveness of colchicine intake. Differential diagnosis with a wide range of febrile conditions was performed. Daily subcutaneous therapy of interleukin 1 inhibitor (iIL1) at a dose of 100 mg was used as a diagnostic marker to confirm the diagnosis of PF. As a result of the therapy, a rapid (within a few hours after injection) relief of the current attack of the disease, normalization of serum CRP levels, and further complete control over the disease (no relapses) were achieved. Our observation shows that a positive response to iIL1 therapy can serve as a diagnostic marker of PF.

Objective: to analyze the safety of rituximab (RTM) in children with various rheumatic diseases.Materials and methods. The retrospective study included 81 pediatric patients with a confirmed diagnosis of rheumatic disease. Data on the safety of RTM were analyzed for all patients who received at least one infusion of the drug. All patients underwent a standard clinical, laboratory and instrumental examination in accordance with the verified diagnosis before the appointment of RTM therapy. The dose of RTM for administration was calculated based on 375 mg/m 2 of body surface area, the drug was administered once a week for 1 to 4 consecutive weeks, depending on the number of CD19 lymphocytes determined after the infusion, and the tolerability of therapy.Results. Among the patients included in the study, 38 (46.9%) were with systemic lupus erythematosus (SLE), 16 (19.75%) – with juvenile idiopathic arthritis (JIA), polyarticular variant (14 (87,5%) of them – RF-positive), 9 (11,1%) – with juvenile idiopathic arthritis with systemic onset (sJIA), 6 (7.4%) – with systemic sclerosus (SSc), 5 (6.2%) – with primary Sjogren’s syndrome, 2 (2.5%) – with juvenile dermatomyositis, 4 (4.9%) – with mixed connective tissue disease, and 1 – with livedoid vasculopathy. 53 (65.4%) patients underwent more than one course of RTM therapy, with a maximum of 10 courses. The total number of infusions was 198. The median time between each course was 182 [156–315] days. RTM was effective in 67 (95%) patients, ineffective in 2 (2.5%) patients with sJIA, 2 (2.5%) patients with SLE and macrophage activation syndrome (MAS).Adverse reactions (AE) of mild to moderate severity were reported in 23 (28.4%) patients, including upper respiratory tract infections – in 7 (8.6%), urinary tract infections – in 2 (2.5%), mild infusion reactions that did not require discontinuation of therapy – in 2 (2.5%), clinically insignificant neutropenia (I–II degree) – in 4 (4.9%), a decrease in IgG levels – in 14 (17.5%) patients (median – 5.5 [4.0; 6.9] g/l). Two patients with sJIA had persistent hypogammaglobulinemia for 3 and 5 years after the last RTM infusion, respectively. The incidence of infections in patients with low IgG levels was 35.7%, and no cases were registered in patients with neutropenia. Serious AE was reported in 16 (19.7%) patients: sepsis – in 4 (4.9%), pneumonia – in 3 (3.7%), herpes zoster – in 1 (1.2%), serious infusion reactions – in 2 (2.5%), serious postinfusion reactions within 3–10 days – in 4 (4.9%) (in 3 patients (3.7%) – MAS, in 1 (1.2%) – hemorrhagic vasculitis); death was registered in 2 cases of SLE and MAS (therapy of RTM was inefficient). In general, various AE were reported in 55.6% of patients with sJIA, 52.6% of patients with SLE, 50% of patients with SSc and juvenile dermatomyositis, and 80% of patients with primary Sjogren’s syndrome. Discontinuation of therapy due to serious AE was observed in 15 (18.5%) patients.Conclusion. Our study demonstrated that RTM therapy is highly effective with an acceptable safety profile in children with rheumatic diseases. The safety data obtained indicate the need for careful monitoring of therapy, primarily taking into account the risk of infection, despite the fact that in this study the frequency of infectious complications was not high. A decrease in IgG level was observed in a small proportion of patients and did not correlate with the incidence of infections.

Objective: to test the hypothesis of a possible relationship between the rs12218 polymorphism of the SAA1 gene and a predisposition to different clinical phenotypes of juvenile idiopathic arthritis (JIA).Patients and methods. Genetic typing of rs12218 polymorphism was carried out in 142 children: 77 of them were diagnosed with JIA, including 30 patients with oligoarthritis (oJIA), 20 with polyarthritis (pJIA), and 27 with systemic onset (sJIA). Sixty five healthy volunteers were included in the control group. The rs12218 polymorphism of the SAA1 gene was investigated using real-time polymerase chain reaction.Results and discussion. A high risk of developing the clinical phenotype of oJIA in carriers of the C mutant allele of the rs12218 T/C polymorphism of the SAA1 gene was established. Statistically significant differences between the clinical phenotypes of oJIA and sJIA in the frequency distribution of genotypes and alleles of rs12218 T/C polymorphism of the SAA1 gene are shown.Conclusion. The results of the studies have confirmed the important role of the rs12218 T/C polymorphism of the SAA1 gene in the formation of susceptibility to clinical variants of JIA.

Seropositive juvenile rheumatoid arthritis (JRA) is the rarest subtype of juvenile idiopathic arthritis (JIA) that is the equivalent of RA in adults and is manifested mainly by a symmetric polyarticular lesion, rapid structural disease progression with the formation of intraarticular erosions, the presence of positive rheumatoid factor (RF), and/or anti-cyclic citrullinated peptide (CCP) antibodies.Objective: to analyze demographic, clinical, and laboratory features of seropositive JRA and drug therapy according to a retrospective 10-year study.Patients and methods. The retrospective study enrolled patients diagnosed with seropositive JRA confirmed according to the ILAR classification, who were treated at the Childhood Rheumatology Department, V.A. Nasonova Research Institute of Rheumatology, from 2010 to 2020. Demographic indicators, data from clinical, laboratory, and instrumental examinations, and performed therapy were assessed.Results and discussion. The investigation enrolled 70 patients, amounting to 6.5% of the total number of patients with all clinical types of JIA. Among them, there was a great preponderance of girls (88.6%); the ratio of boys to girls was 1:7.8. The median age of onset of JRA was 12.2 [7.0; 14.0] years; the median duration of disease at diagnosis verification was 6 [4; 12] months; the median number of active joints at diagnosis of JRA was 16.5 [10.75; 23.25]; oligoarthritis was identified in 11.2% of patients at disease onset (within the first 6 months). During the first year of the disease, radiographic Stages II, III, and IV were defined in 42.9, 50, and 7.1%, respectively. Positive RF was found in 94.3% of patients; there was positivity for anti-CCP antibodies in 78.6%, a combination of positivity for RF and anti-CCP antibodies in 72.9%; only positive anti-CCR antibodies were seen in 5.7%. The median ESR at diagnosis verification was 29 [19.75; 44.5] mm/h; that of CRP was 15.0 [6.9; 34.4] mg/l. The extra-articular manifestations of the disease were found in 18 patients (25.7% of the total number of patients): fever in 5 (7.2%); lymphadenopathy in 17 (24.3%); lung damage in 3 (4.3%); rheumatoid nodules in 2 (2.9%); pericarditis in 1 (1.4%) patient, and uveitis in 1 (1.4%). Sjögren's syndrome was diagnosed in 25.7% of patients; autoimmune thyroiditis in 8.6%. A family history of autoimmune diseases was recorded in 22.8%. Nonsteroidal anti-inflammatory drugs and glucocorticoids were used in 97.1 and 48.6% of patients; respectively; the patients received synthetic disease-modifying antirheumatic drugs (sDMARDs): only methotrexate (MTX) [n=55 (78.6%)], sequentially 2 sDMARDs [n=10 (14.3%)], 3 sDMARDs [n=5 (7.1%)]; biological agents (BAs) [n=66 (94.2%)]. During the first year of the disease, Biological therapy was initiated because of the rapid progression of the erosive process in 78.6% of patients. 64.3% of children took one BA, 18.6 and 7.1% received two and three BAs, respectively. Abatacept (ABC) as the first BA was used most often (45.7%). The reasons for revision of therapy were its secondary inefficiency in most cases and serious adverse reactions in 4 patients (ABC- and infliximab-related infusion reactions in 2 cases and conversion of tubercular tests in 2). The differences in the anti-CCP antibody detection rate were statistically insignificant in the group that used only one BA effectively long and in the group that needed to switch to another BA. When choosing a BA, preference was given to tocilizumab or rituximab (RTM) in patients with seropositive JRA in the presence of systemic manifestations, and high clinical and laboratory activities and to RTM or ABC in those with detected Sjögren's syndrome.Conclusion. Seropositive JRA is a rare subtype of JIA that has an initially unfavorable course. Most patients require early aggressive therapy, including MTX and a BA due to the rapid progression of erosive arthritis. The presence of systemic manifestations and/or Sjögren's syndrome plays a defining role in choosing a specific BA. The presence of anti-CCP antibodies does not affect the selection or change of a BA.

Gastrointestinal (GI) manifestations, such as abdominal pain, nausea, vomiting, and diarrhea, are common autoinflammatory disease (AID) symptoms. The abdominal symptomatology reflecting serositis is one of the most important classification and diagnostic criteria for the classic monogenic AID (MAID) – familial Mediterranean fever (FMF). Failure to timely diagnose FMF frequently leads to unjustified surgical interventions. Other periodic fevers may also present as abdominal symptoms; however, the latter are outside their diagnostic features. These diseases include, first of all, tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Interleukin 1 (IL1) inhibitors serve as the major targeted drugs for the treatment of TRAPS. Russia has registered the IL1 inhibitor canakinumab that prevents the development of organ damages, including those in the GI tract. The paper describes a clinical case of the classic manifestations of TRAPS (fever, rash, periorbital edema, arthritis, and elevated levels of acutephase inflammatory markers) concurrent with severe abdominalgia during attacks and with the development of severe peritoneal adhesions, which led to bowel perforation and emergency surgical intervention. The prolonged persistence of inflammatory attacks before the initiation of therapy, as well as violation of the IL1 inhibitor administration regimen facilitated the development of an urgent exacerbation. Thus, TRAPS should be included in the differential diagnostic circle for patients with severe gastrointestinal manifestations characterized by an attack-like course. These patients need timely prescription of targeted therapy, strict adherence to the dosing and intervals between drug administrations, and careful monitoring to prevent serious complications with the visceral organs, including the gastrointestinal tract, and their immediate correction.

The clinical presentation and outcomes of infection with the novel coronavirus (COVID-19) are characterized by exceptional variability in manifestations, which depend on many factors, one of which is the patient’s age. One of the severe life-threatening manifestations in adults is severe acute respiratory syndrome (SARS-CoV-2), in some cases accompanied by the development of multiple organ failure. During the first two to three months of the COVID-19 pandemic, the global medical community was of the opinion that this disease in children is usually mild and not fatal. However, with the accumulation of new information, it became clear that there is a growing recognition of the existence of multisystem inflammatory syndrome in children, chronologically associated with SARS-CoV-2, which can lead to serious consequences. The article presents the main epidemiological, clinical and laboratory characteristics of the syndrome, as well as discusses the issues of its pathogenesis, differential diagnosis with a number of other acute conditions associated with an dysbalance of cytokines.

The paper is devoted to the assessment of the R92Q (p.Arg121Gln) mutation/polymorphism in the TNFRSF1A gene associated with the monogenic autoinflammatory disease – Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). It gives data on the frequency of this gene in the general population, which is 1.3% and significantly exceeds the incidence of TRAPS. The authors describe the variants of phenotypes associated with its mutation from asymptomatic carriage to the development of a severe systemic autoinflammatory state with persistent febrile fever and a significant increase in the level of acute-phase inflammatory markers that do not respond to standard antirheumatic therapy. They present a clinical case of the high efficiency of the anti-interleukin 1β monoclonal antibody canakinumab in a female patient with a severe TRAPS phenotype, who had the R92Q mutation and hormonal dependence. Canakinumab therapy led to complete relief from all manifestations of the disease and to discontinuation of glucocorticoids. The authors conclude that the decision to prescribe therapy with biological agents should be made on the basis of the clinical severity of the disease rather than a variant of the mutation that caused it.

Juvenile idiopathic arthritis (JIA) is a multifactorial immune-mediated inflammatory disease in childhood, the most common type of rheumatic disease in children. It is characterized by the polygenic type of hereditary predisposition.Objective: to study the association of STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms with the predisposition to certain JIA subtypes in the Russian pediatric population.Patients and methods. The investigation enrolled 177 patients, including 66 patients diagnosed with JIA and 111 healthy unrelated volunteers (a control group). Of the 66 patients with JIA there were 30 (45%) with oligoarthritis: 20 (67%) with human leukocyte antigen B27(HLA-B27)-positive JIA (that was associated with enthesitis, HLA-B27 positive JIA (JIA-B27), 10 (33%) with anterior uveitis concurrent with antinuclear antibody-positive JIA (JIA-uveitis); 20 (30%) with polyarticular JIA (JIA-poly), seronegative for rheumatoid factor; and 16 (24%) with systemic JIA (JIA-sys). As a control for genotyping STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms, the investigators studied 103 and 111 DNA samples from healthy adult volunteers, respectively. STAT4 rs7574865 G/T and IRF5 rs2004640 G/T polymorphisms were investigated using allele-specific real-time polymerase chain reaction (RT-PCR).Results and discussion. In the oligoarticular JIA group, the frequency of the STAT4 T allele was significantly higher than that in the control group (38.3 and 20.4%, respectively; p=0.004). This allele was also significantly more common in the JIA-B27 (35.0 and 20.4%, respectively; p=0.044) and JIA-uveitis (45.0 and 20.4%, respectively; p=0.021) groups compared with the control one. No significant differences were found in the frequency of the mutant STAT4 T allele between the control group and the JIA-sys and JIA-poly groups. Regression analysis showed that the identification of the STAT4 T allele was associated with the high risk of a predisposition to oligoarticular JIA as a whole (odds ratio, OR 2.43; 95% confidence interval (CI) 1.23–4.70; p=0.007), as well as to the antinuclear antibody-positive oligoarticular JIA with uveitis (JIA-uveitis): the risk in T allele carriers was 3.2 times higher than that in the control (OR 3.19; 95% CI 1.09–9.06; p= ). A high risk for predisposition was also found in the JIA-B27 subgroup compared with the control (OR 2.10; 95% CI 0.38–4.60; p=0.070). There were no statistical differences in the frequency of genotypes and alleles of the IRF5 rs2004640 G/T polymorphism between the entire group of JIA as a whole and its individual clinical types, as well as the control group.Conclusion. This pilot study confirmed that the STAT4 rs7574865 G/T polymorphism was associated with the risk of oligoarticular JIA, mainly that of JIA-uveitis and JIA-B27.

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 presents the development of the doctrine of autoinflammatory diseases (AID) in the last decade. Data on interleukin 1, inflammasomes and their role in the development of AID are presented. The paper also contains the data about interferonopathies and, in particular, proteasomal illnesses as a new class of hereditary autoinflammatory diseases. Variety of AID variants, including diseases with the dominance of one system damage (skin, intestines, bones) is shown. Advances in the AID diagnosis and course assessment of are discussed. Relationship of the AID with the problems of fundamental and clinical rheumatology is demonstrated.

The review is devoted to the most common monogenic autoinflammatory disease – familial Mediterranean fever (FML) caused by MEFV gene mutation that occurs mainly in the representatives of certain ethnic groups and manifests itself as recurrent 6–72-hour attacks of pyretic fever accompanied by the phenomena of aseptic peritonitis, pleurisy, arthritis, and inflammatory rash. The disease can lead to a life-threatening complication, such as amyloidosis. FML is noted to be comorbid with a number of other inflammatory diseases: systemic vasculitis, chronic joint inflammatory diseases, and inflammatory bowel diseases. Emphasis is laid on the therapy aspects set out in the 2016 EULAR guidelines. The mainstay of treatment for FML is colchicine that prevents recurrences of the disease, minimizes the risk of amyloidosis, and should be prescribed immediately, once diagnosed. The paper deals with the definition of colchicine resistance that is observed in 5–10% of patients. Biological agents, among which interleukin-1 are most preferred, are now used to treat this category of patients. The high efficacy of these agents in patients with FML has been confirmed in randomized controlled studies.

Tocilizumab (TCZ) is one of the biological agents that are most commonly used in the treatment of juvenile idiopathic arthritis (JIA), especially its systemic variant. The development of neutropenia, which is associated with the use of TCZ and its mechanism of action, requires a detailed study. Based on the analysis of their own results and comparison of the latter with the data available in the literature, the authors analyze the aspects of development of neutropenia during TCZ therapy. Objective: to analyze all cases of neutropenia with the use of TCZ in polyarticular (pJIA) and systemic (sJIA) variants of the disease. Subjects and methods. The open-label prospective study enrolled 27 patients with pJIA and 83 patients with sJIA, who were resistant to prior standard therapy. The treatment duration was 4 to 84 months (median, 22 months for pJIA; 34 months for sJIA). The frequency and timing of neutropenia and the relationship to infection and concomitant/previous therapy were examined. Results and discussion. 22 and 62 patients with pJIA and sJIA, respectively, continued treatment; its median duration was 27.4 [9; 72] months. 7 patients with pJIA and 21 with sJIA, discontinued TCZ due to severe adverse events (n=2 and n=11, respectively) and organizational reasons (n=5 and n=7); in sJIA, therapy was discontinued for sustained remission in two patients and for secondary inefficiency in one patient. At least one episode of neutropenia was observed in 63% of patients with pJIA and in 48.2% of those with sJIA; among them, there was grade 1 neutropenia in 5 and 15 patients, respectively; grade 2 in 6 and 15, grade 3 in 4 and 10, and grade 4 in two patients with pJIA. Neutropenia was more frequently observed in the first months of therapy for pJIA; that was seen in patients with sJIA when the latter reached its inactive status. In 5 patients with sJIA, neutropenia was recorded as a manifestation of macrophage activation syndrome (MAS); no correlation with TCZ infusions was found. Neutropenia was not associated with an increased rate of infections. The use of methotrexate was not significantly related to the low level of neutrophils, whereas the earlier age was associated with the degree and frequency of neutropenia. All cases of neutropenia were recorded in patients with a therapeutic response rate of >50% according to the American College of Rheumatology Pediatric (ACR Pedi) criteria. The findings suggest that there are different mechanisms and periods of neutropenia during TCZ therapy for JIA: 1) benign, transient neutropenia, a predictor of the high efficiency of therapy, develops primarily in the first few days after infusion; 2) neutropenia as a phenomenon of «redundancy» of therapy (more resistant) develops more often in the inactive phase of the disease; 3) neutropenia as a component of MAS, which is associated with its other markers. No relationship was found between neutropenia and an increased risk of infections. TCZ-treated patients need careful clinical and laboratory monitoring, including consideration of a risk for neutropenia and subsequent individual treatment when this condition is identified.

Autoinflammatory diseases (AIDs) are being intensively studied. Molecular genetic testing of patients is of great importance for the diagnosis of AIDs since the basis for its development is pathological mutations that cause innate (antigen-nonspecific) immunity system disorders and the development of inflammation. This also applies to patients with systemic juvenile arthritis (SJA) that has been recently assigned to a group of AIDs due to the great similarity of symptoms. In this connection, the assumption that monogenic AIDs mask SJA in a number of patients was well founded. More than 25 genes, mutations in which lead to AIDs, are known; the NLRP3, TNFRSF1A, and MVK genes are most common and well investigated. These genes cause major monogenic AIDs, such as cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulinemia D/deficit mevalonate kinase syndrome (HIDS).Objective: to identify patients with monogenic AIDs among those with fever, arthralgias, and other manifestations of systemic inflammatory response, including among those with SJA, through molecular genetic testing.Patients and methods. In 2012–2016, molecular genetic testing for mutations in the NLRP3, MVK, and TNFRSF1A genes was carried out within the framework of screening in 184 patients (94 women and 90 men). The investigation enrolled 117 patients with suspected AIDs (Group 1) and 67 patients with SJA (Group 2). The selection criteria were periodic or persistent fever, clinical manifestations of systemic inflammatory response (skin rashes, arthralgias/arthritis, lymphadenopathy, hepatolienal syndrome, serositis, etc.), acute-phase markers when excluding infectious, oncohematologic, and autoimmune causes. SJA was diagnosed based on the ILAR criteria (2001). The patients' age ranged from 6 months to 60 years (mean age, 9.0 years [5; 15]), disease duration, 2 months to 54 years (mean duration, 3.0 [1.0; 8.5])). To identify familial aggregation, genetic tests were also carried out in 18 relatives of the patients with genetically verified AIDs. Molecular genetic analysis was performed in the Laboratory of Hereditary Metabolic Diseases, Research Center of Medical Genetics, Moscow.Results. 15 variants of pathogenic mutations in the studied genes were identified in 43 (23.4%) patients: 31 (16.8%) patients with those in NLRP3, 10 (5.4%) in TNFRSF1A (in a heterozygous state), and 2 (1.1%) in MVK (in a compound heterozygous state). In the AID group, the mutations were detected in 31 (26.5%) patients: 24 (20.5%) in NLRP3, 1 (0.9%) in MVK, and 6 (5.1%) in TNFRSF1A. In the SJA group, the mutations were present in 12 (17.9%) patients: 7 (10.4%) in NLRP3, 1 (1.5%) in MVK, and 4 (5.9%) in TNFRSF1A. The most common mutations in the NLRP3 gene were substitution-missense c. 1049C>T (p.T350M) in 7 (25.9%) patients and low-penetrance mutation c. 2113C>A (p. Q705K) in 13 (28.3%). Examinations established the genetic diagnoses of CAPS in 19 (10.3%) patients, TRAPS in 9 (4.9%), and HIDS in 2 (1.1%). In Group 1, CAPS was identified in 17 (14.5%) patients, of whom 15 had Muckle-Wells syndrome (MWS) and 2 had CINCA/NOMID (Chronic infantile neurologic, cutaneous articular syndrome (CINCA)/Neonatal onset multisystem inflammatory disorder (NOMID); TRAPS and HIDS were present in 6 (5.1%) and 1 (0.9%) patients, respectively. In Group 2, there was CAPS (MWS) in 2 (2.9%) patients, TRAPS in 3 (4.5%), and HIDS in 1 (1.5%). Eleven of the 18 relatives of the patients were ascertained to have mutations and 7 were diagnosed as having AIDs (CAPS in 4, TRAPS in 3).Conclusion. About one-quarter of the patients who have an inflammatory phenotype, including the manifestations of SJA, suffer from monogenic AIDs. Half of them received therapy with the interleukin-1 inhibitor canakinumab, which had a pronounced positive effect. Interpretation of the diagnostic value of low-penetrance mutations is hampered and requires an individual approach. The diagnosis of AIDs should be established in patients having no mutations with great caution, in this case, there is a need for clinical and laboratory criteria for the disease and a thorough assessment of the data of medical history of the patient, and his/her family in particular. The decision to assign these patients to receive lifetime expensive targeted therapy should be well justified.

The paper gives the experience of the V.A. Nasonova Research Institute of Rheumatology in identifying and managing patients with familial Mediterranean fever (FMF). Objective: to describe the features of the disease in patients with FMF in Russia and to compare them with the data obtained in the study of Turkish and Armenian populations with a high incidence of this disease. Patients and methods. The investigation enrolled 23 patients with a documented diagnosis of FMF who met the Turkish pediatric criteria (F. Yalcinkaya et al.) and/or the criteria described by A. Livnech et al. and had two identical mutations (homozygosity) or two different mutations (compound heterozygosity) in the MEFV gene. Among the patients there were 9 men and 14 women. The age of the patients at the time of treatment was 4.5 to 36 years. Their age at onset of FMF was 2 months to 15 years (mean age, 3.2±2.3 years). Results. The examination established that 18 (78.3%) patients were Armenians, 3 were representatives of the North Caucasus peoples (a Darghin woman, an Avar man, and an Ingush/Kabardian man), a man from mixed (Greek/Georgian) marriage, and a Russian woman whose ancestors were Armenian and Jewish. The most common manifestation of FMF were recurrent episodes of fever (22; 95.7%); abdominal pain with fever ranked second (19; 82.6%), followed by chest pain (11; 47.8%), locomotor apparatus lesion (16; 69.6%), and skin lesions (7; 30.4%). The episodes were accompanied by increased levels of acutephase markers in 100% of the patients. There were a high proportion of patients, in whom FMF was concurrent with other rheumatic and autoinflammatory diseases (juvenile chronic arthritis, chronic recurrent multifocal osteomyelitis, and acute rheumatic fever) (7; 30.4%). Twenty-two (95.6%) patients received colchicine; the tumor necrosis factor inhibitor etanercept was prescribed in 2 (8.7%) patients with comorbidity; there was a pronounced therapeutic effect. Conclusion. Although the majority of our patients were Armenians, the disease was also identified in those belonging to the peoples of the North Caucasus and Transcaucasia and in one Russian female patient. There has generally been a fairly typical picture of the disease. The considerable frequency of joint damage and the high proportion of patients with comorbid rheumatic diseases have engaged our attention. From a diagnostic point of view, of importance is the elevated level of acutephase markers during a disease attack, which in combination with the clinical and ethnic characteristics of patients allows the diagnosis of FMF to be suspected.

Autoinflammatory diseases (AIDs) are characterized by periodic, sometimes self-limiting attacks that appear as fever and clinical symptoms resembling rheumatic ones, in the absence of autoimmune or infectious diseases. The group of AIDs encompasses a broad spectrum of nosological entities; some of them have been recently dealt with by rheumatologists.Objective: to define the spectrum of AIDs in the practice of a pediatric rheumatologist from the results of visits to the Russian Federal Rheumatology Center.Subjects and methods. The investigation enrolled patients who had visited the V.A. Nasonova Research Institute of Rheumatology in 2007 to 2015 for fever and other signs of a systemic inflammatory process in order to specify their diagnosis and to rule out infections, blood cancer, and other diseases. All underwent conventional rheumatologic examination, HLA Class A typing, and molecular genetic testing.Results and discussion. 101 patients aged 6.5 months to 60 years with AIDs were identified over 9 years and diagnosed as having the following diseases. Familial Mediterranean fever (FMF) was detected in 17 patients (the female to male (M/F) ratio was 6:11); Behсet's disease (BD) in 25 children (M/F, 14:11), cryopyrin-associated periodic syndromes (CAPS) in 17 patients, including Muckle–Wells syndrome in 13 (M/F, 4:9); chronic infantile neurologic cutaneous articular and neonatal onset multisystem inflammatory disease (CINCA/NOMID) syndrome in 4 (M/F, 3:1), periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome in 17 (M/F, 10:7), hyper-IgD syndrome/mevalonate kinase deficiency syndrome in 3 (M/F, 0:3), tumor necrosis factor receptor periodic syndrome (TRAPS) in 7 (M/F, 4:3), undifferentiated AID in 14, and Blau syndrome in one patient. The patients with BD were rather ethnically diverse: among them, there were representatives of North Caucasian peoples, Tatars, Uzbeks, Moldavians, and others; there were 7 ethnic Russians. There was a preponderance of Armenians among FMF patients (15/17). Ethnic Russians were predominant among the patients with other nosological entities. HLA-B5 antigen was found in 9 (36%) patients with BD. Molecular genetic analysis confirmed the diagnosis in virtually all the patients with monogenic AIDs.Conclusion. The most common AIDs in our practice were BD, FMF, CAPS, and PFAPA. The patients with CAPS were closest in clinical and laboratory presentations to those with rheumatic disease, particular to those diagnosed with systemic juvenile arthritis and this disease should be kept in mind in differential diagnosis. Our practical experience indicated that targeted therapy with interleukin 1 inhibitors was effective in CAPS patients. This treatment is able to substantially improve an initial poor prognosis.

Cryopyrin-associated periodic syndromes (CAPS) are the most prominent representatives of monogenic autoinflammatory diseases (AIDs). They are characterized by a concurrence of fever, rash, and other symptoms that are accompanied by disabling or life-threatening complications. Based on the current guidelines for the management of patients with AIDs and on their own experience, the authors have elaborated a diagnostic algorithm for CAPS, which can optimize their differential diagnosis with systemic juvenile arthritis and other AIDs and the early use of effective therapy and management tactics. Interleukin-1 inhibitors are target agents, by which one can monitor activity and prevent complications. The given algorithm will be able to improve the timely diagnosis of CAPS and to optimize treat-to-target treatment and management in patients.

Objective. To perform a prospective investigation of clinico-laboratory and sonographic picture of juvenile arthritis (JA) onset, to follow up its evolution during the first years of the disease, to prove the program of appropriate treatment.Material and methods. 128 pts with early JA (61% girls and 39% boys aged 1,5 to 16 years) were included. Disease duration varied from 2 weeks to 6 months. General health, joint status, disease activity, functional class (Steinbroker), systemic and organ disturbances, laboratory activity indices, immunologic parameters (ANF, RF) were assessed. Antibodies to cyclic citrullinated peptide (ACCP) were evaluated in 38 pts by immunofluorescence method (IFM) with commercial kits “Axis Shild Diagnostics Limited, UK”, antibodies to modified citrullinated vimentin (MCV) were assessed in 60 pts by IFM with commercial kits “Orgentec” (Germany). Pts were examined every 3 months, the main investigations were repeated after 6, 12 and 24 months. Accuracy of the diagnosis was checked at every examination.Results. Mono- oligoarticular variant of onset was found in 68,6% polyarticular – in 21,4%, systemic – in 10% of pts. Knee and ankle joints were involved first (61% and 24% respectively), later – wrist (13%) and hand joints (17%). Morning stiffness was absent in 85% of pts. 37% of pts had ANF and 13,2% - RF. 10,5% were ACCP positive and 28,3% – MCV positive. Antibodies correlated with polyarticular variant of JA and RF. Reactive arthritis was the preliminary diagnosis in 39% and JRA – in 21% of pts at inclusion. Later Juvenile chronic arthritis was the most frequent diagnosis (73-80%). Disease modifying antirheumatic drugs were prescribed early (before 6 months) in 53% of pts. Exacerbations of the disease appeared in 1/3 of pts, more frequently – in pts with polyarthritis. After 12 months functional class 1 remained in 71,4% of pts.Conclusion. Stabilization of pathological process or remission can be achieved in most children with early JA. Pts with polyarthritis sometimes need intensification of treatment (administration of biological agents or change of DMARD. Evaluation of ACCP and MCV can be helpful for diagnosis and prognosis of the disease. Questions of diagnosis, terminology and early verification of diagnosis need further discussion.

The paper presents the clinical characteristics of Behcet's disease (BD) in Russian children, generally accepted criteria for BD, and diagnosis statement. The investigation is based on an observation of 17 children who met the international criteria for BD and were treated at the V.A. Nasonova Research Institute of Rheumatology in 2004 to 2013. One-third of children had a compromised family history; about 30% of the patients were ethnic Russian. The age at BD onset ranged from infancy to 16 years. The interval between disease onset and diagnosis was 1 to 10 years. The clinical symptoms at onset represented mostly frequently aphthous stomatitis and its accompanying fever and much less frequently aphthae of the genitalia. Furtherthe pathological process involved other organs and systems. In advanced stage of disease, there was already a clinical syndrome encompassing aphthous stomatitis, a genital ulcerative process, and lesions of the eye, skin, gastrointestinal tract, and less often central nervous system. The manifestations of the disease in different combinations can be concurrent with each other, showing a mosaic pattern. Treatment of children with BD included glucocorticoids, colchicine, azathioprine, and, if clinically indicated, tumor necrosis factor-α inhibitors. Their efficacy is discussed. The pediatric aspects of BD, which are presented in this paper, are first published in Russian medical press

Interleukin 1 (IL 1) is the main mediator for many auto inflammatory diseases (AID). Cryopyrin-associated periodic syndromes (CAPS) became the first diseases, for which the efficacy of IL 1 inhibitors was shown with a high degree of evidence. Canacinumb (totally human monoclonal antibodies to IL 1 is registered in Russia since 2011 for treating CAPS. At the moment research is being conducted to evaluate the efficacy and tolerance to IL 1 inhibitors in patients with other AIDs. The accumulated experience and scarce randomizedcontrolled studies demonstrate a successful usage of IL 1 inhibitors in colchicine-resistant patients with family Mediterranean fever with the cupping of inflammation attacks, reducing the acute phase activity and also in patients with other monogenic (TRAPS, HIDS and others) and multifactorial pathologies (systemic juvenile arthritis, Stilk disease in adults, gout etc.). Using the IL 1 inhibitors, especially canacinumab, in patients with different AIDs has shown good tolerance and a high efficacy in all patients with no correlation to the age, according to Russian and world research. Thus, canacinumab, thanks to its therapeutic abilities, has broad perspectives in terms of lightening the disease course, improving survival, life quality and the overall prognosis.

Muckle-Wells syndrome (MWS) is an autoinflammatory disease belonging to a group of cryopyrin-associated periodic syndromes (CAPS). It is considered to be one of the intermediately severe conditions among CAPSs and to be intermediate between the severest syndrome – Chronic I nfantile Onset Neurologic Cutneous Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID) and the mildest syndrome–Familial Cold Autoinflammatory Syndrome (FCAS). MWS, like all cryopyrinopathies, is caused by a mutation in the NLRP3 (CIAS1) gene; it shows an autosomal inheritance pattern. There are reports on familial MWS cases in the foreign literature; such examples are sporadic in Russia. The given clinical observation clearly demonstrates a genetically verified familial case of MWS in a mother and her daughter in a Russian population and shows how long (occasionally during tens of years or more) the complete complex of the disease may be formed. The results of treatment with the interleukin-1 inhibitor canakinumab in both patients are also given. The high good tolerability and high efficacy of the drug against the clinical manifestations of MWS and acute-phase markers are shown.

Tumor necrosis factor (TNF) receptor-1-associated periodic syndrome (TRAPS) is a classical autoinflammatory syndrome (AIS). The paper describes repeated cases of TRAPS in an ethnic Russian family. Molecular genetic examination of a 9-year-old boy, his mother and his grandmother has revealed the heterozygous mutation of c151C

Interleukin (IL) 1βis a major mediator of cryopyrin-associated periodic syndrome (CAPS). In this connection, the experience with IL-1 inhibitors used in patents with CAPS is being accumulated worldwide. Canakinumab was approved by FDA and EMEA in 2009 to treat CAPS and registered in the Russian Federation for this in 2011. The drug has been shown to be highly effective and well tolerated by patients with CAPS.Objective: to present Russia's experience in using the IL-1 inhibitor canakinumab in children with CAPS.Subjects and methods. The trial enrolled 6 CAPS patients, including 4 with Muckle-Wells Syndrome (MWS) and 4 with chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), among whom there were 5 female patients aged 3.5 to 40 years and 1 male patient aged 17 years. Two patients (a 17-year-old daughter and her 40-year-old mother) were stated to have a familial MWS case. The duration of the disease was 3.5 to 33 years. All the patients underwent a molecular genetic analysis for mutations in the NLRP3 (CIAS1) gene. Four patients with MWS were found to have Thr436Ile and Thr438Ile mutations; the mother and her daughter had Thr350Met mutations; no mutations were detected in 2 patients with CINCA/NOMID. At the study, one female patient with MWS took gluco-corticoids (GC) in a dose of 0.1 mg/kg; the others received symptomatic therapy with nonsteroidal antiinflammatory drugs. Canakinumab was injected subcutaneously every 8 weeks in a dose of 4 mg/kg for patients with a body weight of 15 kg. By now, 2 patients with MWS received 7 injections of the drug (a 48-week follow-up); 2 patients with CINCA/NOMID had its 6 injections (a 40-week follow-up) and 2 patients with MWS had 2 injections (a 10-week follow-up).Results. All the patients showed a significant clinical improvement: recovery; elimination of fever, rash, and eye symptoms; and a reduction in the levels of acute-phase markers. The effect retained throughout the follow-up. GC could be completely discontinued in the female patient with MWS. No adverse events were observed in any case.Conclusion. The experience in using canakinumab in the patients with CAPS showed the high efficacy and good tolerability of the drug. The decrease in acute-phase markers was slower in the patients with CINCA/NOMID, the most severe form of CAPS.

The paper reviews the publications dealing with Schnitzler syndrome, a rare autoinflammatory disease, and describes the authors’ own clinical observation. It describes the first Russian experience in successfully using the interleukin-1 inhibitor canakinumab to treat this disease.

Aim. To determine the possibility of using the serum proinflammatory calcium-binding protein, or calgranulin C (S100A12), to assess activity and therapeutic efficiency in patients with periodic disease (PD) and other familial periodic fevers (FPFs). Subjects and methods. Thirty-five patients with PD and other FPDs, which were verified by molecular genetic study, were examined. In accordance with the disease activity, the patients were divided into 2 groups. The investigators determined the concentration of S100A12 by solid-phase enzyme immunoassay and that of other acute-phase inflammatory markers (erythrocyte sedimentation rate (ERT), neutrophil counts, and fibrinogen and C-reactive protein (CRP) concentrations). Results. The serum concentration of S100A12 in the stage of disease activity was 466.7 (265.22—851.7) ng/ml, which was significantly higher than in remission (244.29 (118.93—409.85) ng/ml (p=0.000002). The highest S100A12 concentrations were noted in the patients with PD; these were 758.95 (434.80—1035.95) ng/ml; the S100A12 level in the majority of PD patients even during remission remained moderately higher. An investigation of the relationship of A100A12 to genetic variants found no differences between the patients homozygous for M694V and those with other genotypes (p=0.37). Estimation of the time course of therapy-induced changes in the serum S100A12 concentration revealed its considerable reduction (р=0.0018). However, normalization of S100A12 levels was not achieved in PD. The remaining increased S100A12 concentration in these patients may be suggestive of the activity of PD despite the absence of its clinical manifestations. S100A12 as a highly sensitive marker allows more exact evaluation of the anti-inflammatory effect of therapy. The S100A12 identification of the subclinical activity of autoinflammatory diseases made all the more important since traditional inflammatory markers, such as ERT, CRP, fibrinogen, and leukocyte counts, are less sensitive for these purposes. In our study, these markers were within the reference range in remission. No differences were found in the S100A12 levels between the groups with and without amyloidosis (p=0.62). Conclusion. S100A12 is a highly sensitive marker for the activity of autoinflammatory diseases and the efficiency of their therapy. The serum level of S100A12 in PD may be used to diagnose the subclinical activity of inflammation, which is of importance in monitoring the risk of amyloidosis.

In recent years, increasing attention has been paid to the problem of preserving the genetic diversity of farm animals and poultry. However, an indispensable condition for the economic feasibility of preserving any breed is not only its uniqueness, but also the possibility of practical use. An example is the Russian snow-white breed of chickens in the VNIIGRZh bioresource collection. It was developed by breeding of Russian white chickens for thermal resistance at low temperature conditions, as well as for resistance to neoplastic diseases. Currently, this breed is specialized for the purposes of the bio-industry (raw materials for the production of embryonic viral vaccines). The change in the direction of breeding work led to a modification of the genetic structure of the population. Constant selective pressure on one particular trait can lead to a decrease in variability around the genomic regions associated with that trait. Therefore, understanding the genetic mechanisms leading to phenotypic differentiation requires the identification of regions in the genome that were under selection pressure. The study of runs of homozygosity (ROH) rates can provide useful information about the history of population selection, as well as allow for a better understanding of the genotype-phenotype relationship by discovering genes that are or were under selection pressure. In ROH islands specific to two generations of chickens, the most relevant candidate genes associated with adaptive traits are annotated. It has been established that genetic analysis based on changes in ROH can be used to characterize the genetic profile of chickens and to change the structure of the population under the influence of selection pressure. These data are especially important to take into account when evaluating qualitative phenotypic features, such as the adaptive capabilities of chickens.

The article is devoted to the problem of increasing the resistance of chicks from hatching to the age of 3 weeks to infectious diseases by technological methods. Dosed low-temperature exposure to the embryo during the sensitive period of early embryogenesis was proposed as an impact factor; influenza vaccine virus was used as a test virus for experimental infection of embryos. It was found that in the embryos after cooling, the titer of the virus was significantly lower by 1.5-12.0 times (p

The article is devoted to the life and various aspects of the activities of the outstanding diplomat Prince Alexey B. Lobanov-Rostovsky (1824–1896). The name of Lobanov-Rostovsky was not mentioned in literature until the first decade of the 21st century. Then Lobanov began to be remembered thanks to the efforts of his descendant Prince Nikita D. Lobanov-Rostovsky who initiated a number of studies about the prominent diplomat. A fundamental monograph on Prince Lobanov-Rostovsky has now been prepared. His international activity as Ambassador Extraordinary and Plenipotentiary took place at the most difficult political points at that time — twice in Constantinople (1859–1863; 1878–1879), as well as in London (1879–1882) and Vienna (1882–1895). He always managed to solve the most pressing problems of his time using skillful diplomatic tools. He received the post of Deputy Minister of the Ministry of Internal Affairs during the challenging period of restructuring of social and public institutions in Russia. It was the era of the so called Great Reforms of Emperor Alexander II. By offering him this position, the emperor took into account Prince’s intellectual scale, strategic foresight and tactical flexibility. During 11 years of activity in this field (1867–1878), Prince Lobanov-Rostovsky often performed the duties of a minister. During this time, the legal norms of the state and its relations with society significantly improved. In 1870, Alexey B. Lobanov-Rostovsky received the honorary position of State-Secretary of His Imperial Majesty, that is, the emperor's personal speaker, the position he held until the end of his life. Both Emperor Alexander II and Nicholas II treated Lobanov-Rostovsky with special warmth. Lobanov-Rostovsky managed to conclude the Russian-Turkish final Peace Treaty of 1879, which put an end to the war between Russia and Turkey. This agreement gave Russia significant moral and material results and marked the beginning of the autonomous Principality of Bulgaria, that led to Bulgarian statehood. Lobanov-Rostovsky’s work as Foreign Minister for 18 months (1895–1896) brought Russia fruitful results on the world stage and was highly appreciated both in Russia and in the world. The article talks about the different sides of the prince’s extraordinary personality. A true polymath, proficient in the Russian antiquity, he became a bibliophile, collector, genealogist and historian. He carefully commented on the historical documents he discovered and for 14 years (1871–1885) systematically published in special historical journals. The article examines the memoirs of contemporaries about the diplomat, as well as the latest research about him.

Taking these prospects into account, the integration potential of Russia in the conditions of gradual trade and economic unity of the ASEAN countries can be considered in the aspect of formation of new strategic opportunities for interaction with the integration environment of Eurasia on the basis of investments in infrastructure development within the framework of the Eurasian Economic Union (EAEU). The advantages and disadvantages of the digital platforms and the characteristic features of international DLPs are highlighted. Based on the analysis, the necessity of developing an international digital platform in the EAEU is justified in the context of the development of international digital logistics platforms within the framework of the Eurasian Economic Union.

Modern poultry breeding in Russia is one of the fastest growing sectors of agriculture, but the prosperity of the industry is almost entirely dependent on supplies of breeding material from abroad. Russia practically has no its own breeding base in both egg- and meat-type commercial crosses of chickens. Most of the domestic commercial crosses that had occupied leading positions in Russian poultry breeding have been lost now. More than 90 % of commercial lines of breeding stocks in Russia are imported. Foreign poultry breeding companies merge into transnational holdings engaged in multi-species breeding of farm animals, which allows them not to depend on market conditions in the industry. The reverse side of such a consolidation on a global scale is a decrease in the genetic diversity of poultry and a high level of inbreeding in commercial chicken lines. In these circumstances, there is a real biological danger for the preservation of these lines due to the potential susceptibility of “monocultures” to new diseases, which can eliminate the genetically homogeneous population. Any selection system is based on an assessment of the breeding value of potential parents. Its purpose is to obtain, as far as possible, the most accurate forecast of the genetic value of an individual and the productive qualities of its progeny. These requirements are optimally met by the BLUP methodology, in which molecular genetics (SNP) data can be successfully integrated, which allows supplementing the statistical analysis with genomic selection technologies. This is especially true for traits that cannot be measured, or can only be measured in one sex, or only at the end of the productive period. The inclusion of genomic selection methods in breeding programs makes it possible significantly increase the selection efficiency for the main economical traits of chickens. The main task in the Russian breeding poultry industry is the creation of its own competitive breeding base, not inferior to Western commercial crosses in terms of productivity. To create poultry breeding centers and grandparents/parents-breeding farms the state support is needed. It is also necessary to develop and implement innovative methods in the field of genomic selection, as well as software and information systems and specialized selection computer programs for processing and analyzing meta-data.

Successes in Russian politics of the XIX century are significant thanks to the efforts of diplomats Alexei Borisovich Lobanov-Rostovsky and Nikolai Pavlovich Ignatieff. In studies of the XX century, they are almost forgotten. Ignatieff is an experienced tactician, a supreme professional who owns a military affair. He had diplomatic cunning. Sometimes Ignatieff showed adventurism. Basically, these qualities provided him good luck in the diplomatic field. However, Ignatieff was not enough historical knowledge. It was in diplomatic negotiations during the Russian-Turkish war of 1878-1879 that this lacuna prevented his success. He insisted on the idea of pan-Slavism, not taking into account all international factors. The diplomat did not take into account the historical features of the Ottoman Empire, Europe’s interest in its power and influence, that is, the historical totality of the international system of counterweights. Lobanov-Rostovsky - strategist. And it was inherent evasiveness, skillful ability to convince of the correctness. However, the role of historical education in his diplomatic practice was enormous. In a more deliberate line of conduct at the conclusion of the final Treaty of Constantinople, he was helped by fundamental «background knowledge» that allowed him to adequately assess the geopolitical situation. The Prince was engaged in history from an early age. The hobby grew into professional occupations. For 16 years he published historical essays in leading historical journals. He had access to secret documents of the Russian Empire thanks to the trust of Emperor Alexander II. Lobanov used to work with primary sources. History has taught him that sometimes you need to act quickly, and in some situations, to exercise the greatest caution. In the situation of the Russian-Turkish war, he set himself only specific goals. If the San Stefano peace Treaty of 1878, signed by count Ignatieff, is well known, then the final Treaty of Constantinople, signed by Prince Lobanov-Rostovsky, is still very little mentioned. Meanwhile, after the Treaty of San Stefano, there were events that undermined its positive results. A “Berlin treatise of the great powers” in 1878 deprived Russia of a significant part of the acquisitions that it has achieved under the Treaty of San Stefano. Here Lobanov faced important General and specific tasks. To solve them, the new Ambassador had to have absolutely unique characteristics. In addition to the enormously developed ability Lobanov to build relationships with people: personal goodwill and the confidence of Alexander II; the respect in the higher Turkish circles; the location to him of the Sultan, who himself appealed to the Emperor with a request to appoint Ambassador Lobanov. The totality of personality traits and circumstances led to a convincing success, which was the final Treaty of Constantinople in 1879, which resulted in an independent state-the Autonomous Principality of Bulgaria.