Background: Immunosuppressive therapy (methotrexate and biological agents) for juvenile idiopathic arthritis (JIA) is associated with an increased risk of severe infections, higher infection rates, treatment interruptions, failure to achieve disease remission, and recurrent disease flares. Our study aimed to evaluate the safety and efficacy of simultaneous immunization with 13-valent polysaccharide conjugate vaccines (PCV13) against S. pneumoniae (SP) and Hemophilus influanzae type b infections (HibV) in children with JIA without systemic manifestations. Methods: A total of 371 non-systemic JIA patients who received 13PCV and HibV were included in this prospective cohort study. In every patient, we evaluated clinical, laboratory, anti-SP, and anti-Hib IgG antibodies before vaccination, three weeks after, and six months after, and all adverse events (AEs) were collected during the study. The number and duration of acute respiratory infection (ARI) episodes and requirements for antibacterial treatment and AE six months before and after the baseline were collected. Results: The levels of the Ig G anti-SP and anti-Hib antibodies increased in the 3 weeks after vaccination; then, anti-SP antibodies slightly decreased and anti-Hib antibodies remained increased during the whole study, as well as in a part of the patients with a protective titer. During the study, there were no patients with significant flares, and the main JIA outcomes gradually decreased during the trial. The number of patients with uveitis remained equal, as well as the part of the patients with active, low-active, and inactive uveitis. There was no significant rise in the hs-CRP or S100 protein after the vaccination. Previous or ongoing treatment with non-biological (p = 0.072) and biological (p = 0.019) disease-modified anti-rheumatic drugs affected the Hib and did not affect the anti-SP protective titer at the end of the study. Within 6 months following vaccination, the number of ARI episodes (p < 0.001) and the number of courses of antibacterial treatment (p < 0.0001) decreased twice. The median duration of ARI episodes decreased four times (p < 0.0001). Mild AEs (injection site reactions and short-term fever episodes) were found in 58 (15.6%) patients with JIA, and 1 patient (0.2%) developed an SAE. Conclusions: Simultaneous vaccination against pneumococcal and Hib infections reduces the frequency and duration of episodes of ARI, as well as the number of courses of antibacterial drugs, and does not lead to significant JIA flares. The number of reported AEs is consistent with what was expected.

Background: Some patients with juvenile idiopathic arthritis (JIA) can successfully undergo withdrawal of treatment with anti-tumor necrosis factor alpha (anti-TNF-α) therapy, which may reduce economic and treatment-related burdens and the potential morbidity of treatment for at least 6 months. Currently, no guidelines exist on the appropriate withdrawal of anti-TNF-α therapy once clinically inactive disease (CID) has been achieved. This study aimed to assess the possibility of withdrawing anti-TNF-α therapy in children with non-systemic JIA after achieving long-term clinical remission. Methods: This single-center retrospective cohort study included data from 137 non-systemic JIA patients treated with anti-TNF-α therapy (etanercept or adalimumab) and having maintained CID for at least 24 months during treatment. Demographic, laboratory, and treatment data were collected at JIA onset, at the initiation of anti-TNF-α therapy, every 6 months during therapy, and at the time of disease flare. Anti-TNF-α therapy was discontinued abruptly after discussing it with the patients and their families in each case. Outcomes were assessed using standard criteria for remission in JIA (ACRpedi and Wallace criteria). Results: Following withdrawal of TNF-α inhibitors, 93/137 patients (67.9%) experienced a disease flare, with a median time to flare of 7 months (3; 14). Thirty-two percent of patients remained in remission for a median of 63 months. Absence of flare during the first 22 months after discontinuation was associated with prolonged biologic-free remission (odds ratio 682; 95% CI 38.6–12,062; p < 0.0001), with 83% sensitivity and 100% specificity (area under the ROC curve 0.967). Most flares involved arthritis (76%) and/or uveitis (24%), primarily affecting knees, ankles, and wrists. Inflammatory markers were generally lower at flare compared to baseline. Biological therapy was resumed in 84/93 patients (90.3%), achieving at least a 50% improvement according to ACRpedi criteria within 3 months and remission according to Wallace criteria within 6 months. Conclusion: Over two-thirds of patients with non-systemic JIA who achieve CID experience a flare within seven months of anti-TNF-α discontinuation. Re-initiation of biologic therapy is effective in restoring remission. These results indicate that prolonged biologic-free remission is possible in a subset of patients, highlighting the need for individualized withdrawal strategies and careful post-discontinuation monitoring.

The efficacy of JAK-kinase inhibitors in autoimmune diseases is due to the peculiarities of their pathogenesis, the involvement of various cytokines that trigger the cascade of inflammatory reactions, enhance the transcriptional response of disease-induced or disease-associated genes and potentiate the production of proinflammatory cytokines. Only tofacitinib is currently approved for use in pediatric rheumatic diseases. Given the literature data on the efficacy of other JAK-kinase inhibitors in adult rheumatic diseases, we assume the possibility of their use in pediatric patients. Objective. To evaluate the efficacy and safety of selective JAK-kinase inhibitor upadacitinib in children with rheumatic diseases. Patients and methods. Data on 85 pediatric patients with various variants of juvenile idiopathic arthritis (JIA) (n = 64) and systemic connective tissue lesions (SCTL) (n = 21) treated with upadacitinib were included in this retrospective study. Initiation of therapy was carried out on the basis of the rheumatology department of the Research Institute of Pediatric Rheumatology of the Federal State Autonomous Institution "Children's Health Research Center" of the Ministry of Health of Russia (Moscow) in the period from May 2022 to July 2023. Descriptive statistics methods were used to assess the efficacy of upadacitinib therapy, comparative analysis was performed using the Wilcoxon criterion. Therapy outcomes in the group of patients with JIA were evaluated by the percentage of improvement according to pediatric criteria of the American College of Rheumatology, achievement of inactive disease stage according to C.Wallace criteria and JADAS-71 activity index, in the group of patients with SCTL – by the dynamics of clinical and laboratory activity parameters, as well as steroid-saving effect. Results. In patients with JIA without systemic manifestations treated with upadacitinib for 3 months (15/54), 30% improvement in ACR Pedi criteria was recorded in 13/15 (87%), 50% in 12/15 (80%), 70% in 11/15 (73%), and 90% in 10/15 (66%) patients; after 6 months. – 30th; 50th; 70th; 90% improvement in 14/15 (93%), 14/15 (93%), 13/15 (87%), 13/15 (87%) patients, respectively. Inactive disease stage according to C.Wallace criteria after 3 months was achieved in 5/15 (33.3%) patients, after 6 months. – у 11/15 (73,3%). In patients with systemic JIA the efficacy of therapy after 3 months was evaluated in 3/10 patients: 2/3 achieved JADAS remission (1 of them – stage of inactive disease according to C.Wallace criteria), in 1 patient the disease activity increased against the background of hip arthroplasty. After 6 months (assessment of outcomes is available in 3/10 patients): 1 patient achieved JADAS remission, 1 patient achieved 50% improvement according to ACR Pedi criteria, 1 patient showed increased disease activity when attempting to reduce the dose of glucocorticoids (GCS). In the group of patients with SCTL, the majority of patients were able to reduce clinical and laboratory disease activity and the demand for oral GCS. Conclusion. The use of upadacitinib in children in rheumatic diseases is highly effective and safe. In patients with refractory course of the disease it is possible to achieve a decrease in disease activity and remission, to reduce the dose of GCS. Key words: systemic connective tissue lesions, systemic juvenile idiopathic arthritis, upadacitinib, juvenile idiopathic arthritis, Janus kinases

Objective. To evaluate the pharmacokinetics (PK), efficacy, and safety of the direct interleukin-6 inhibitor olokizumab (OKZ) when used in adolescent patients with active juvenile idiopathic polyarthritis (JIA), with ineffectiveness or intolerance to methotrexate. Patients and methods. The results of OKZ therapy at a dose of 64 mg every 4 weeks during 24 weeks of the open-label study were analysed. The parameters of PK, efficacy, dynamics of serum concentration of C-reactive protein (CRP), adverse events (AEs) were evaluated. Results. Sixteen patients were included in the study, of whom 13 (81.2%) received OKZ therapy up to and including week 24. The PK profile was consistent with that of adults with rheumatoid arthritis. By week 16, 12 (80%) patients achieved an ACRpedi30 response, 11 (73.3%) achieved ACRpedi50, inactive disease was achieved by 2 (13.3%) patients. The response was maintained until week 24. There were no exacerbations of pJIA. Patients with baseline CRP values >10 mg/L and in the subgroup naive to biologic anti-rheumatic drugs had a trend towards a higher response (p > 0.05). Twenty-three AEs were reported in 12 (75.0%) patients, all of mild to moderate severity, with infections being the most frequent AE in 6 (37.5%) patients. No serious AEs or deaths were reported. Conclusion. Treatment with OKZ demonstrated a reduction in pJIA activity and good tolerability. The safety profile was consistent with that of interleukin-6 blockers, and the OKZ PK was consistent with that of adults with rheumatoid arthritis. Key words: juvenile idiopathic arthritis, genetically engineered biological drugs, interleukin-6 inhibitor, olokizumab, clinical

New coronavirus infection (COVID-19) is an acute respiratory disease caused by the SARS-CoV-2 coronavirus. Tixagevimab+cilgavimab has been developed for the prevention and treatment of COVID-19. The purpose of this research was to evaluate the safety of the use of the two-component drug of monoclonal antibodies to SARS-CoV-2 (tixagevimab+cilgavimab) for pre-exposure prophylaxis of the new coronavirus infection in children with rheumatic diseases (RDs). Materials and methods used: a single-center retrospective study with prospective stage had been carried out that included 300 pediatric patients aged 12 to 18 y/o with RDs. The safety of pre-exposure prophylaxis of COVID-19 was assessed based on the dynamics of clinical and laboratory parameters as well as the total indices of RD activity. The effectiveness of pre-exposure prophylaxis was assessed based on recording the incidence of the new coronavirus infection. Safety and effectiveness were assessed after 3, 6, and 9 months after the administration of tixagevimab+cilgavimab drug. Results: no statistically significant increase in RDs activity was registered during 9 months of observation after pre-exposure prophylaxis of COVID-19. On the contrary, in patients with various types of juvenile arthritis, systemic lupus erythematosus and juvenile ankylosing spondylitis during the observation period against the background of antirheumatic therapy, a statistically significant decrease in the activity indices was registered - JADAS71 (p<0.001, p=0.002, p=0.030), SELENA-SLEDAI (p<0.001, p=0.027, p=0.570) and JSpADA (p=0.009, p=0.205, p=1.000), respectively; in patients with juvenile dermapolymyositis, systemic sclerosis and systemic vasculitis - a tendency to decrease in activity indices - DAS (p=0.002, p=0.050, p=0.193), J4S (p=0.840, p=0.720, p=1.000), PVAS (p=0.120, p=0.230, p=1.000 for the new and p=0.360, p=1.000, p=0.860 for the constant attributes), respectively. The new coronavirus infection was suffered by 6/300 (2%) patients within 9 months after pre-exposure prophylaxis. Conclusion: pre-exposure prophylaxis of COVID-19 with the two-component drug of monoclonal antibodies to SARS-CoV-2 (tixagevimab+cilgavimab) may be considered as both effective and safe and can therefore be suggested to pediatric patients with RDs.

Background: The introduction of biological drugs into clinical practice for the treatment of children with systemic juvenile idiopathic arthritis (sJIA) allows disease control but increases the risk of infectious events. Infectious events cause immunosuppressive therapy interruptions, leading to disease flare and life-threatening complications, namely macrophage activation syndrome. Our study aimed to evaluate the efficacy and safety of simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) in children with sJIA. Methods: This study included 100 sJIA patients receiving immunosuppressive therapy who were simultaneously vaccinated against pneumococcal and Haemophilus influenzae type b (Hib) infections. The mean age of disease onset was 5.5 years. The median age at vaccination was 10 ± 4.5 years. Clinical and laboratory parameters of sJIA activity, immunization efficacy, and safety, including anti-SP and anti-Hib IgG antibodies, as well as all vaccination-related adverse events (AEs), were recorded in every patient before, 3 weeks after, and 6 months after vaccination. Results: At the time of vaccination, 29% of patients did not meet the criteria for the inactive disease stage, as defined by C. Wallace: active joints were present in 34.5% of patients, systemic manifestations (rash and/or fever) were present in 41.3%, and 24.2% of patients had solely inflammatory laboratory activity. The protective titer of anti-SP and anti-Hib IgG antibodies was detected in the majority of patients 3 weeks after vaccination (100% and 93%, respectively). The results remained unchanged (99% and 92%, respectively) for 6 months of follow-up, compared to the baseline (91% and 37%, p = 0.000001). Anti-SP IgG and anti-Hib titers raised from 48.3 (18.2; 76.5) and 0.64 (0.3; 3.2) U/mL at the baseline to 103.5 (47.3; 185.4) and 4 (3.5; 4.2) U/mL at D22 and 105 (48.7; 171.8) and 4 (3.8; 4) U/mL (EOS), respectively. Immunosuppressive therapy regimens (combined therapy or biological disease-modifying antirheumatic drug monotherapy) did not influence the immunogenic efficacy of vaccination. The incidence of infectious complications (p = 0.0000001) and antibiotic prescriptions (p = 0.0000001) decreased by more than two times, to 29.9 and 13.8 events per 100 patient months, respectively, within 6 months after vaccination—the average duration of acute infectious events was reduced by five times after immunization (p = 0.0000001). Vaccination did not lead to disease flare: the number of patients with active joints decreased by half compared to the baseline, and the number of patients with systemic manifestations decreased by six times. All vaccine-associated adverse events were considered mild and resolved within 1–2 days. Conclusions: Simultaneous vaccination against pneumococcal and Hib infections in sJIA children is an effective and safe tool that reduces the number and duration of infectious events and does not cause disease flare-ups.