In most cases, COVID-19 has a favorable outcome. However, the risk of developing critical forms of the disease, including secondary hemophagocytic lymphohistiocytosis HLH (cytokine storm syndrome), remains high. This dictates the interest in studying pathogenetic mechanisms, features of the clinical picture, laboratory and instrumental criteria for covid-19 disease. The article analyzes the causes of acute respiratory distress syndrome and multiple organ failure as manifestations of HLH. The necessity of monitoring signs of hyperinflammation (ferritin, C-reactive protein, etc., biomarkers of inflammation) and activation of thrombosis is substantiated, in order to make timely decisions about the beginning of pathogenetic therapy. However, there are limitations for routine testing of the level of Pro-inflammatory cytokines. Information about the diagnostic criteria of HLH is summarized, and the expediency of these criteria for establishing secondary HLH, which has complicated the course of COVID-19, is emphasized.

Background. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) characterized by hyperinflammation and a variety of clinical and laboratory manifestations. This condition is also referred to as macrophage activation syndrome (MAS) in patients with rheumatic diseases, including those with sJIA. In this article, we use the term sHLH. Approximately 40% of sHLH cases are asymptomatic, especially in patients who receive biologicals. Thus, the development of a prognostic model and identification of early sHLH markers in sJIA patients will enable timely initiation of anti-inflammatory and immunosuppressive therapy. Objective. To develop a prognostic model and identify early sHLH markers in sJIA patients. Methods. This study included 100 sJIA patients who were examined and treated in the Department of Rheumatology, National Medical Research Center for Children's Health between August 2010 and May 2021. A total of 114 sHLH episodes were registered among study participants. We analyzed medication history, as well as clinical and laboratory parameters reflecting the activity of sHLH and sJIA as potential early markers of sHLH. Multivariate logistic regression analysis was used to assess the predictive value of these markers for sHLH development. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each factor to evaluate its significance. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of the model. Results. We analyzed a number of factors as potential early sHLH markers, including medication history (treatment with oral or injectable glucocorticoids (GCs) before sHLH, immunosuppressants (methotrexate, cyclosporine, or leflunomide), and biologicals (tocilizumab, canakinumab, adalimumab, etanercept)), clinical signs (fever, rash, hepatomegaly, splenomegaly, lymphadenopathy, myalgia, hemorrhagic syndrome, central nervous system (CNS) lesions, kidney lesions, lung lesions, heart lesions), and laboratory parameters (hemoglobin, absolute count of red blood cells (RBCs), white blood cells (WBCs), neutrophils, lymphocytes, and platelets, erythrocyte sedimentation rate (ESR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), creatinine, blood urea, c-reactive protein (CRP), ferritin, triglycerides, procalcitonin (PCT), total protein, albumin, blood electrolytes (sodium, potassium, chlorides, iron), coagulation parameters (Quick prothrombin, thrombin time, prothrombin time, international normalized ratio (INR), partial thromboplastin time (APTT), D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, and protein C). Our prognostic model demonstrated that the following variables were significant predictors of sHLH in sJIA patients: lymphadenopathy, red blood cell count <4.34 × 106 cells/mL, platelets <208 × 103 cells/mL, serum chlorides <101.9 mmol/L, and serum lactate dehydrogenase >412 Units/L. The specificity of the model was 98.0%; the overall accuracy was 95.6%. The area under the ROC-curve (AUC) was 0.954 ± 0.027 (95% CI 0.902–1.000; р < 0.001). Conclusion. The most reliable prognostic markers of sHLH in sJIA patients are undoubtedly heterozygous mutations in the genes of primary (familial) hemophagocytic lymphohistiocytosis. In addition to that, lymphadenopathy, decreased RBC and platelet count, decreased serum level of chloride, and elevated serum LDH in sJIA patients can be interpreted as early sHLH markers and, therefore, considered as an indication to enhance anti-inflammatory and immunosuppressive therapy. Key words: secondary hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, early markers, prognostic model

Secondary hemophagocytic syndrome (SHS) is a life-threatening complication of systemic juvenile idiopathic arthritis (SJIA, syn.: systemic-onset juvenile idiopathic arthritis). Timely treatment of SHS can improve outcomes and reduce mortality rates. There has been little evidence worldwide on the effectiveness of therapy for SHS in patients with SJIA, including the use of genetically engineered biopharmaceutical drugs (GEBDs). Objective. To evaluate the efficacy of different treatment regimens for SHS in patients with SJIA. Patients and methods. This study included 100 patients with SJIA complicated by SHS who were examined and treated at the rheumatology department of the National Medical Research Center for Children’s Health (Moscow) from August 2010 to May 2021. All patients met the criteria for SJIA and SHS diagnosis. The efficacy of different therapy regimens for SHS was assessed according to treatment response criteria and achievement of the clinically inactive status of SHS. The Kaplan-Meier survival analysis was used to investigate the proportion and duration of the period prior to SHS recurrence (relapse-free interval) after the end of therapy, including the use of GEBDs for the treatment of SJIA. The proportion of relapse-free survival cases and the duration of relapse-free interval were assessed within 36 months in 79 of 100 patients (89/114 (78%) SHS cases). Results. Medical records of 100 patients with 114 cases of SHS were retrospectively studied. In 84/114 (73%) cases, SHS developed in patients not receiving GEBDs (“biologically naïve”), and in 30/114 (26%) cases, SHS developed against the background of GEBD therapy (“biologically non-naïve”). Combination therapy, which included intravenous (dexamethasone 17.9 [10; 20] mg/m2/day or methylprednisolone 12.1 [5; 20] mg/kg/day) and oral (prednisolone 0.9 [0.5; 2] mg/kg/day) glucocorticosteroids (GCs), as well as cyclosporine (CsA) at a dose of 4.5 [2; 7] mg/kg/day and normal human immunoglobulin (syn. intravenous immunoglobulin; IVIG) at a dose of 1.5 [0.3; 2] g/kg. In 24/114 (21%) cases, GEBDs were prescribed for the treatment of SHS: in 11 (10%) – tocilizumab, in 8 (7%) – canakinumab, and in 5 (4%) – rituximab. Hemophagocytic syndrome resolved in 111/114 (97%) cases, lethal outcome was registered in 3/114 (3%) cases. Conclusion. Response to treatment and inactive SHS status achievement in the shortest possible time were recorded when using a treatment regimen that included intravenous and oral administration of GCs, as well as CsA and IVIG, regardless of the background use of GEBDs for the treatment of SJIA. In “biologically naïve” patients, response to treatment developed faster, and the proportion and duration of relapse-free interval were significantly greater than in “biologically non-naïve” patients. Key words: secondary hemophagocytic syndrome, systemic juvenile idiopathic arthritis, treatment, genetically engineered biopharmaceutical drugs

The incidence of rheumatic diseases has been constantly growing during the last 20 years, which necessitates regular assessment of the healthcare quality for these patients and identification of the most significant problems and ways to address them. Juvenile idiopathic arthritis (JIA) is one of the most frequent disabling rheumatic diseases in children. The incidence and prevalence of JIA allow us to use this disorder to evaluate the organization of rheumatology care in general in terms of its accessibility and quality, as well as measures to improve it. This article reviews JIA epidemiology, characteristics and problems of healthcare organization for children with rheumatic diseases in the Russian Federation and other countries. Key words: healthcare organization, rheumatic diseases, health care, juvenile idiopathic arthritis

Rationale. Children with rheumatic diseases receiving immunosuppressants and/or genetically engineered biopharmaceutical drugs (GEBDs) and/or glucocorticosteroids (GCs) are at high risk of developing severe and/or long-term symptoms of novel coronavirus infection. The possibilities of pre-exposure prophylaxis of COVID-19 in this patient population are significantly limited due to the risks of insufficient immunogenicity of the vaccine in the presence of secondary immunodeficiency developed under the conditions of immunosuppressive therapy and exacerbations/increasing activity of the underlying disease after vaccination. The use of a combination of two monoclonal antibodies against SARS-CoV-2 (tixagevimab/cilgavimab) may become a priority method for the pre-exposure prevention of COVID-19 in children with rheumatic diseases. Objective. To evaluate the efficacy and safety of using a combination of two monoclonal antibodies against SARS-CoV-2 (tixagevimab/cilgavimab) in the pre-exposure prophylaxis of novel coronavirus infection in immunocompromised pediatric patients with rheumatic diseases. Patients and methods. This study enrolled 234 patients aged 12 to 17 years and 11 months with body weight ≥40 kg and a confirmed diagnosis of rheumatic disease. Indications for the use of tixagevimab/cilgavimab for the pre-exposure prophylaxis of COVID-19, as stated in the medication information leaflet, included individuals not infected with SARS-CoV-2 and who had no contact with a person infected with SARS-CoV-2. An additional inclusion criterion was a moderate or severe decrease in immunity due to a pathological condition and/or the use of immunosuppressive medications in patients observed at the National Medical Research Center for Children’s Health and the Morozov Children’s City Clinical Hospital. The tixagevimab/cilgavimab medication was administered intramuscularly as two consecutive injections of each component at a dose of 300 mg (150 mg of each component) to 153 patients, 600 mg (300 mg of each component) to 81 patients. Endpoints used in this study were: • considering efficacy: the incidence rate of novel coronavirus infection in 3 and 6 months after pre-exposure prophylaxis with tixagevimab/cilgavimab in children with rheumatic diseases; • considering safety: exacerbation rates of the underlying disease after pre-exposure prophylaxis with tixagevimab/cilgavimab; the nature, frequency, severity, and outcomes of adverse events, including serious ones directly related to the drug administration. Results. This prospective observational cohort study involved 234 patients with rheumatic diseases, among them were 140 (60%) girls and 94 (40%) boys aged 12 to 17 years and 11 months (median (IQR): 14.79 (13.00, 16.17) years); 168 patients (71.79%) with various types of juvenile arthritis, 66 (28.21%) with systemic connective tissue disorders (SLE, dermatomyositis, systemic sclerosis, vasculitis), 171 (73.08%) with the underlying disease in remission and 63 (26.92%) with exacerbations. All patients received disease-modifying antirheumatic drugs (DMARDs) (methotrexate/mycophenolate, mofetil/cyclophosphamide/sulfasalazine) and/or biological DMARDs (inhibitors of TNF-α/CD20+B-lymphocytes/IL-1, IL-6/IL-17 receptor/T-cell co-stimulation), or targeted synthetic DMARDs (tofacitinib/upadacitinib); 71 (30.34%) patients received oral GCs; 160 (68.37%) patients received 2 to 4 antirheumatic drugs. Before inclusion in the study, 140 (59.83%) children had COVID-19. Within 3 months of preexposure prophylaxis, 2 cases of COVID-19 were reported (0.85%). No exacerbations/increasing activity of the rheumatic disease were recorded in patients immunized in the remission/exacerbation stage with tixagevimab/cilgavimab at doses of 300 mg and 600 mg, respectively. No adverse events directly related to the drug administration were observed. Conclusion. Preliminary results of a prospective observational cohort study indicate a high efficacy and a favorable safety profile of a combination of two monoclonal antibodies against SARS-CoV-2 (tixagevimab/cilgavimab) in the pre-exposure prevention of novel coronavirus infection in immunocompromised pediatric patients with rheumatic diseases. Key words: COVID-19, SARS-CoV-2, monoclonal antibodies, pre-exposure prophylaxis, tixagevimab, cilgavimab, rheumatic diseases, children