Search

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 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.

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.

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.

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 randomized controlled 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.

Аутовоспалительными заболеваниями (синдромами) человека (Human autoinflammatory disease - HIDS) называют гетерогенную группу редких, генетически детерминированных состояний, характеризующихся непровоцируемыми приступами воспаления и проявляющихся лихорадкой и клинической симптоматикой, напоминающей ревматическую, при отсутствии аутоиммунных или инфекционных причин [1]. Аутовоспалительные синдромы дебютируют чаще всего в детском возрасте, иногда на первом году жизни, и поэтому являются в первую очередь педиатрической проблемой. Большинство заболеваний из указанной группы относятся к редкой патологии. Однако это во многом обусловлено трудностью диагностики и плохим знанием указанных заболеваний педиатрами во всём мире. Между тем как реальный шанс встретить пациента с подобной патологией есть у каждого практикующего педиатра, в том числе в России.

Objective. To determine frequency of anti-cyclic citrullinated peptide antibodies (ACCP) and anti-modified citrullinated vimentin antibodies (AMCV) elevation and their diagnostic significance in children with early juvenile arthritis (JA). Material and methods. ACCP were evaluated in serum of 80 pts with early JA (36 girls, 44 boys, mean age 8,5±5,03 years), AMCV — in 85 pts with early JA (49 girls and 36 boys) aged from 1,5 to 16 years (mean age 8,7±4,9 years). Disease duration in all children was less than 6 months. Control group included 54 grown up pts with early rheumatoid arthritis (RA), 27 - with undifferentiated arthritis (UDA) and 37 conditionally healthy children. АССР was assessed by immuno-enzyme assay (IEA) with commercial kits “Axis Shield Diagnostics" (Great Britain), upper normal limit 5,0 U/ml. AMCV was examined by IEA with commercial kits “Orgentec Diagnostics” (Germany), upper normal limit — 25 U/ml. Results. ACCP was elevated in 7 children with early JA (8,8%). Frequency was higher than in healthy children but lower than in grown up pts with early RA and comparable with UDA. In juvenile rheumatoid arthritis (JRA) ACCP were more frequent than in juvenile chronic arthritis (JCA). Concentration was higher in rheumatoid factor (RF) positive pts with polyarticular JA. AMCV level was elevated in in 23 (27,1%) pts with early JA (more frequent than in healthy donors but less frequent than in grown up pts with early RA and UDA). AMCV was significantly more frequent in JRA than in JCA and in RF positive than in RF negative pts. AMCV concentration in JA was higher than in healthy children but lower than in grown up pts with RA. It was also higher in RF+ than RF- JA. ACCP and AMCV correlated with swollen joint count, tender joint count and RF. AMCV also correlated with ESR and CRP. Conclusion. In pts with early JA ACCP and AMCV are equally or more frequent than RF. In spite of low sensitivity they have high specificity for JRA in contrast to JCA. Assessment of ACCP itself or in combination with RF and AMCV is of significant importance for prognosis of polyarticular joint damage with risk of significant functional disability development and timely administration of proper quite often aggressive therapy in early stage of the disease.

Objective. To assess efficacy of hospital stage of treatment including rehabilitation methods in pts with juvenile idiopathic arthritis (JIA) evaluating changes of some measures of functional status at admission and at discharge. Material and methods. 56 pts with different variants of JIA admitted to the pediatric department of the Institute of Rheumatology of RAMS and treated with medicaments and rehabilitation methods. Correction of anti-inflammatory therapy influencing functional status (NSAIDs dose increase, intra-articular injections of glucocorticoids) was done in 36 pts. In the rest of pts treatment with DMARDs was changed. Mean duration of hospital stay was 20 days. At admission and at discharge following measures were recorded: pain on VAS, dynamometry, 25 m walking time, contracture angle and amplitude of movement of joint causing disability and treated with rehabilitation methods (mean summated measures were assessed, localization was not considered). Results. Significant change of pain (29,04 mm+2,9 mm vs 9,92 mm±l,6 mm), contracture angle (19,33o±l 1,12 о vs 10,33 о ±8,34 о) and movement amplitude (71,5 о ±38,52 о vs 90,71 о ±38,52 о). Significant improvement (movement amplitude increase from 68,6±42,4 to 85,3±41,0 and angle of deformation decrease from 15±5,8 to 8,5±7,4) was achieved in 20 pts without correction of treatment influencing functional status. Conclusion. Functional status of pts with JIA improved as a result of complex treatment with medicaments and active rehabilitation methods. Importance of rehabilitation treatment in pts with JIA during hospital stay was shown.

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.

Objective. 7 cases of AHA syndrome (arthralgia, arthritis, hives, angioneuroticedema) in children described. Literature and own data are presented. Possible pathogenetic mechanisms, clinical symptoms and treatment are discussed.

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

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.

Objective: to estimate quality of life in adolescents with juvenile arthritis (JA) on the basis of an analysis of the results of SF-36 questionnaire interviews. Subjects and methods. Two groups of patients including 85 adolescents with JA (Group 1) and 34 apparently healthy individuals of their age (Group 2; controls) were examined. There were 63% of females among the patients. Systemic, polyarticular, oligoarticular, and juvenile ankylosing spondylosis JA (JAS) were diagnosed in 16 (19%), 34 (40%), 24 (28%), and 11 (13%) patients, respectively. The examinees' mean age was 15.2±1.1 years (range 14-17 years); the mean disease duration was 6.1±4.6 years (range 1-15 years). The control group comprised 73% of females; the mean age was 15.2+1.1 years (range 14-17 years); the adolescents went to school, they had neither musculoskeletal diseases nor release from physical training classes. The SF-36 questionnaire validated for those older than 14 years was used. Results. In Group 1, physical functions, physical activity, body pain, general health condition, and social functions were significantly worse than those in the controls. At the same time, viability, mental health, and emotional activity proved to be (statistically insignificantly) better in Group 1 than in the controls. In Group 1, the boys had better values of functional functions, physical activity, viability, and mental development while the girls had better values of body pain, general health condition, social functions, and emotional activity. In the control group, all these parameters were lower in the girls than in the boys. In Group 1 boys, all the parameters were significantly worse than those in the healthy peers (controls). Group 1 girls with JA had worse physical functions, physical activity, and pain, but better general health and social functions than the controls. Differences were found in the groups of patients with different types of JA: the parameters were significantly worse in those with systemic and oligoarticular types and better in those with JAS. Conclusion. The application of the SF-36 questionnaire could reveal significantly reduced physical functions in the patients with JA as compared to their healthy peers. It is expedient to use this questionnaire for intergroup comparative studies if sufficient clinical material is available.

The mechanisms of action of currently used genetic engineering biological agents (GEBAs) include inhibition of cytokines, interleukins, and T cells and depletion of B cells. GEBAs were originally accessible mainly for the treatment of refractory juvenile idiopathic arthritis (JIA), including systemic-onset JIA (Still's disease), which allowed one to do away with the long-term use of high doses of glucocorticoids or cytostatics. Since 2000, a number of randomized double-blind placebo-controlled and open-label pilot studies have convincingly demonstrated the efficacy of GEBAs in children and adolescents. Although the tumor necrosis factor-a (TNF-a) inhibitors etanercept and adalimumab are chiefly used to treat refractory polyarticular JIA, interleukin 1 and 6 blockers showed satisfactory results in treating systemic JIA. Abacept is regarded as a treatment option for patients with polyarticular JIA when disease modifiers and TNF-a inhibitors are ineffective. The place of rituximab in the management of JIA has not certainly defined so far. However, GEBA therapy cannot completely cure the disease as before despite the progress achieved. GEBAs have potentially a number of serious side effects, among which there are severe infections and there is a risk of developing malignancies and autoimmune processes. Their administration requires careful monitoring to reveal the early development of serious adverse reactions, thus preventing a poor outcome.

The paper describes approaches to using cyclosporin A (CsA) in juvenile arthritis (JA). It shows the benefits of combination basic therapy with CsA and methotrexate included into a treatment regimen mainly for systemic JA and JA involving the eye (uveitis) versus monotherapy with the above drugs. Attention is drawn to that the oral dose of glucocorticoids may be decreased when CsA is incorporated into the treatment regimen. CsA is shown to be of value as the drug of choice for the therapy of such a menacing complication of systemic JA as the macrophage activation syndrome

Хронические артриты у детей являются важной проблемой современной педиатрии в силу того, что эти тяжелые заболевания существенно нарушают качество жизни ребенка и его родителей, требуют немалых экономических затрат на лечение и нередко приводят к инвалидности ребёнка. Этиология этих заболеваний в настоящее время окончательно не расшифрована, существует лишь ряд более или менее обоснованных гипотез на этот счет. Лечение ювенильных артритов (ЮА), несмотря на значительные успехи, достигнутые в последние десятилетия, также далеко от совершенства: подбор медикаментозных средств зачастую производится эмпирически, не всегда врачу удается контролировать патологический процесс и предотвратить серьезные функциональные нарушения. Любой значительный прорыв в терапии хронических артритов у детей может быть достигнут только при условии прогресса в понимании патогенеза этих заболеваний и механизмов действия лекарственных препаратов, направленных на конкретные звенья патологического процесса. Появление в последние годы новых классов лекарственных препаратов, так называемых биологических противовоспалительных агентов, особенно остро ставит вопрос об участии определенных механизмов в формировании различных форм ЮА, без чего невозможно грамотное назначение данных лекарств у конкретного больного.

Objective: to estimate the concentration of anti-cyclic citrullinated peptide antibodies (CCPA), the frequency of their increase, and their diagnostic value in children with early juvenile arthritis (JA). Subjects and methods. Sera from 80 patients (36 girls and 44 boys) aged 1,5 to 16 years (mean age 8,5+5,03 years) who had early JA were tested for CCPA. The diagnosis of juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA) was made in 19 and 57 patients, respectively; the duration of JA being < 3 months in 4. The systemic type of JA was present in 8 (10%) children; the polyarticular and oligoar-ticular types in 37 (46,2%) and 35 (43,8%) children, respectively. The duration of the disease in all children did not exceed 6 months. A comparison group comprised 54 adult patients with early rheumatoid arthritis (RA), 27 with undifferentiated arthritis (UDA), and 37 apparently healthy children. The concentration of CCPA was measured by immunoassay using the commercial оAxis Shield Diagnosticsп kits (United Kingdom), the upper normal range being 5 U/ml. Results. The higher levels of CCPA were revealed in 7 (8,8%) children with early JA. Their frequency was higher than that in healthy children; however, it was lower than that in adult patients with RA and comparable with UDA. CCPAs were detected more frequently in JCA and rheumatoid factor (RF)-positive patients. Higher concentrations were observed in patients with RF-positive polyarticular JA. There were correlations of CCPA with the number of swollen and tender joints, RF. Conclusion. In patients with early JA, the detection rate of CCPA is significantly higher than that in healthy children and comparable with that of RF. CCPAs have a high specificity for the diagnosis of JRA (an independent nosological entity within JA) are a risk factor of polyarthritis. The early detection of CCPA alone or in combination with RF in JA patients may serve the basis for the early use of active, frequently aggressive therapy.