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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.

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.

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 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.

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 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.

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

Objective. To study clinical and laboratory manifestations of different variants of juvenile arthritis (JA) at the disease onset and during prospective two-year follow up. Material and methods. The study was performed as a part of Institute of Rheumatology early arthritis examination program RADIKAL. 130 pts with early JA (60,7% - girls) with disease duration from 2 weeks to 6 months (mean 2,9±1,6 months) aged 1,5- 16 years (mean 7,9±5,0 years) were included. 13 (10%) pts had systemic, 45 (34,6%) – polyarticular and 72 (55,4%) – olygoarticular variant of JA. General state, joint status, systemic and organ manifestation as well as immunological parameters (ANF, RF), disease activity, functional class (by Steinbrocker and CHAQ) were assessed at baseline, and after 6, 12, 24 months of follow up. Results. Oligoarticular variant prevailed at onset and after 2 years (57,6%-55,6%). Systemic features were noted in reduced form as single manifestations. Morning stiffness was absent in half of children and lasted more than 1 hour in 16,4% of pts. After 2 years number of pts with morning stiffness significantly decreased and its duration diminished. Rheumatoid nodules appeared in 1 pt after 1 year. Uveitis developed in 7 children (5,3%) and to the end of follow up it appeared in 2 more pts. Most of pts had minimal or moderate functional disability (FK 1,2 and CHAQ 0,1-1,5) during follow up. Disease activity at onset did not exceed 1 or 2 stage (80,2%) and after 2 years the disease was not active in half of pts. To the end of follow up remission was achieved in 59% of pts, more often in those who received disease modifying anti-rheumatic drugs. In 23,2% of pts mostly in those with polyarthritis JA continued to recur independently on treatment. Conclusion. Timely administered complex therapy hampered disease progression, induced remission and improved quality of life in most children with JA. Pts with olygoarthritis had most favorable course of the disease. Pts with polyarthritis required early administration of aggressive therapy.