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Background: Pediatric lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE) in children, determining the outcomes of the disease. There are no standardized treatment protocols for pediatric LN, and the role of biologics has not yet been conclusively defined. Objectives: analyze the safety and efficacy of rituximab biosimilar BCD020 in pediatric patients with lupus nephritis. Methods: in a retrospective cohort study, the data from the case histories of 25 patients with LN (10 boys and 15 girls) with an onset age of 13 (9–16) years, who failed conventional non-biologic treatment or developed corticosteroid dependence/toxicity, were included. The diagnosis was made using Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Rituximab biosimilar BCD020 was prescribed in a dosage of 375 mg/m2 every week (2–4 infusions) with repeated courses every 6–12 months (2–4 infusions) according to disease activity, B-cell depletion, and IgG levels. The dynamics of clinical and laboratory data, the activity of the disease by SLEDAI, and corticosteroid doses were assessed at the onset and during the rituximab trial. Results: The main patient's characteristics were: Pre-rituximab non-biologic conventional treatment included: cyclophosphamide 15 (60%), MMF 8 (32%), azathioprine 3 (12%), hydroxychloroquine 12 (48%), and pulse therapy of methylprednisolone followed by oral methylprednisolone 25 (100%). The time before rituximab was 7.0 (3.0–24.0) months, and the whole observation period was 7.0 (0; 24) months. The initial pre-rituximab treatment slightly reduced SLEDAI levels and the proportion of patients with LN. A significant reduction of SLEDAI, the anti-dsDNA level, proteinuria, hematuria, C4 complement, ESR, and the median corticosteroid dose by 80% from the initial value, as well as the proportion of patients without corticosteroids, was observed after rituximab administration. Two deaths were observed due to catastrophic SLE with macrophage activation syndrome, accompanied by a severe infection (invasive aspergillosis, n = 2). Three patients developed serious adverse events: pneumonia (n = 2), transient agranulocytosis (n = 1) after the third rituximab infusion, and meningitis, caused by Listeria monocytosis, after the first rituximab infusion. Eight patients received antibacterial treatment for different respiratory infections without hospital admissions. Conclusions: Rituximab biosimilar BCD020 showed effectiveness in LN, whereas previous non-biologic treatment was insufficiently effective. Randomized controlled trials are required to evaluate the efficacy and safety of rituximab and evaluate the benefits when compared with conventional SLE treatment. [ABSTRACT FROM AUTHOR]

Background Juvenile systemic lupus erythematosus (JSLE) is a severe life-threatening disease. The place of rituximab in JSLE management is still undefined. The early biologic intervention might improve disease's outcomes. Aim of study To assess the advantages of early rituximab administration compared with late. Material and methods In the retrospective cohort study the information about 36 JSLE patients, whom rituximab biosimilar BCD020 was initiated were included. All patients were divided in two groups: early start of rituximab (less than six months from onset) and late start (more than one year). We compared initial disease characteristics at onset, on the baseline (BL)—start of rituximab and end of the study—(EOS) - 12 months, and treatment characteristics. Results The time gap between early and late rituximab administration was 19 months. There were no differences in disease profile at onset, except higher SLEDAI and MAS frequency in early rituximab group. Baseline differences were: lower C3, C4, higher SLEDAI and oral daily corticosteroids dosage. At the end of the study, patient whom rituximab was prescribed early had more impressive changes in SLEDAI, e.g. 100% of patients decreased SLEDAI, compared with 79% in late rituximab group. The detailed information about disease activity and treatment outcomes in both groups are in the table. There were no differences in adverse events between groups, except more impressive signs of corticosteroid toxicity in group of late rituximab administration. Conclusion Early administration of rituximab biosimilar made it possible to control the JSLE activity faster and reduce the dose of corticosteroids effectively. There were no differences in adverse events, except signs of corticosteroid toxicity in group of late rituximab initiation. This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075–15-2022–301). Ethics The study was approved by the Ethical Committee of the Saint-Petersburg State Pediatric Medical University (Protocol No1/3 from 11/Jan/2021). There were no violations of patient's rights according to the Declaration of Helsinki. OA03 Table 1. Parameter.  Early start of rituximab (n = 16).  Late start of rituximab (n = 19).  P -value.  Time before rituximab, months  3 (2; 6)  22 (14; 36)  0.00001  SLEDAI, BL, points  22 (15; 26)  10 (6; 16)  0.003  SLEDAI, EOS, points  2 (0; 4)  2 (0; 6)  1.0  SLEDAI changes from BL, points  -18 (-13; -24)  -6 (-14 -14)  0.0006  Patients, improved SLEDAI, %  16 (100)  15 (79)  0.05  SLEDAI changes from BL, %  85 (81; 100)  64 (14; 100)  0.099  Daily corticosteroids, BL, mg/kg  1.0 (0.6; 0.1)  0.3 (0.2; 0.8)  0.027  Daily corticosteroids, EOS, mg/kg  0.1 (0.08; 0.16)  0.1 (0.06; 0.2)  0.842  Median daily corticosteroids change from BL, %  85 (60; 88)  68 (33; 90)  0.436  Improvement in SLEDAI from BL        SLEDAI30  16 (100)  14 (74)  0.027  SLEDAI50  16 (100)  13 (68)  0.014  SLEDAI70  15 (94)  9 (47)  0.004  SLEDAI 90  7 (44)  7 (37)  0.678  SLEDAI100  5 (31)  6 (32)  0.984  Parameter.  Early start of rituximab (n = 16).  Late start of rituximab (n = 19).  P -value.  Time before rituximab, months  3 (2; 6)  22 (14; 36)  0.00001  SLEDAI, BL, points  22 (15; 26)  10 (6; 16)  0.003  SLEDAI, EOS, points  2 (0; 4)  2 (0; 6)  1.0  SLEDAI changes from BL, points  -18 (-13; -24)  -6 (-14 -14)  0.0006  Patients, improved SLEDAI, %  16 (100)  15 (79)  0.05  SLEDAI changes from BL, %  85 (81; 100)  64 (14; 100)  0.099  Daily corticosteroids, BL, mg/kg  1.0 (0.6; 0.1)  0.3 (0.2; 0.8)  0.027  Daily corticosteroids, EOS, mg/kg  0.1 (0.08; 0.16)  0.1 (0.06; 0.2)  0.842  Median daily corticosteroids change from BL, %  85 (60; 88)  68 (33; 90)  0.436  Improvement in SLEDAI from BL        SLEDAI30  16 (100)  14 (74)  0.027  SLEDAI50  16 (100)  13 (68)  0.014  SLEDAI70  15 (94)  9 (47)  0.004  SLEDAI 90  7 (44)  7 (37)  0.678  SLEDAI100  5 (31)  6 (32)  0.984  Open in new tab OA03 Table 1. Parameter.  Early start of rituximab (n = 16).  Late start of rituximab (n = 19).  P -value.  Time before rituximab, months  3 (2; 6)  22 (14; 36)  0.00001  SLEDAI, BL, points  22 (15; 26)  10 (6; 16)  0.003  SLEDAI, EOS, points  2 (0; 4)  2 (0; 6)  1.0  SLEDAI changes from BL, points  -18 (-13; -24)  -6 (-14 -14)  0.0006  Patients, improved SLEDAI, %  16 (100)  15 (79)  0.05  SLEDAI changes from BL, %  85 (81; 100)  64 (14; 100)  0.099  Daily corticosteroids, BL, mg/kg  1.0 (0.6; 0.1)  0.3 (0.2; 0.8)  0.027  Daily corticosteroids, EOS, mg/kg  0.1 (0.08; 0.16)  0.1 (0.06; 0.2)  0.842  Median daily corticosteroids change from BL, %  85 (60; 88)  68 (33; 90)  0.436  Improvement in SLEDAI from BL        SLEDAI30  16 (100)  14 (74)  0.027  SLEDAI50  16 (100)  13 (68)  0.014  SLEDAI70  15 (94)  9 (47)  0.004  SLEDAI 90  7 (44)  7 (37)  0.678  SLEDAI100  5 (31)  6 (32)  0.984  Parameter.  Early start of rituximab (n = 16).  Late start of rituximab (n = 19).  P -value.  Time before rituximab, months  3 (2; 6)  22 (14; 36)  0.00001  SLEDAI, BL, points  22 (15; 26)  10 (6; 16)  0.003  SLEDAI, EOS, points  2 (0; 4)  2 (0; 6)  1.0  SLEDAI changes from BL, points  -18 (-13; -24)  -6 (-14 -14)  0.0006  Patients, improved SLEDAI, %  16 (100)  15 (79)  0.05  SLEDAI changes from BL, %  85 (81; 100)  64 (14; 100)  0.099  Daily corticosteroids, BL, mg/kg  1.0 (0.6; 0.1)  0.3 (0.2; 0.8)  0.027  Daily corticosteroids, EOS, mg/kg  0.1 (0.08; 0.16)  0.1 (0.06; 0.2)  0.842  Median daily corticosteroids change from BL, %  85 (60; 88)  68 (33; 90)  0.436  Improvement in SLEDAI from BL        SLEDAI30  16 (100)  14 (74)  0.027  SLEDAI50  16 (100)  13 (68)  0.014  SLEDAI70  15 (94)  9 (47)  0.004  SLEDAI 90  7 (44)  7 (37)  0.678  SLEDAI100  5 (31)  6 (32)  0.984  Open in new tab [ABSTRACT FROM AUTHOR]

Background/Purpose: Uveitis often is the only initial clinical manifestation of JIA for years. There are no reliable markers of JIA-associated uveitis and impossibility to overcome ocular barriers impede diagnosis and treatment leading to blindness. During the last years the number of proteins identified in tears increased from 200 (Herber et al., 2001) of only 17 (Zhou et al., 2003) different molecular weights (MW) to 491 (de Souza et al., 2006) with 80 chemokines, cytokines, and growth factors (Sack et al., 2005). Objective of the study is to reveal protein markers of JIA-associated uveitis in tears using high-resolution mass-spectrometry and hierarchical clustering methodology. Methods: Standard clinical protocol was used to diagnose uveitis and JIA. Tear samples drawn from 17 JIA-patients with uveitis, 4 JIA-patients without uveitis, 3 patients with systemic vasculitis, 4 patients with idiopathic uveitis and 3 healthy subjects were analyzed. Tears were collected on a filter paper, digested with trypsin and the peptides were purified on Zip tips. The samples were loaded to nano C18 column attached to Shimadzu nano LC coupled in-line to LTQ Orbitrap XL tandem mass spectrometer (Thermo Fischer Scientific, GA, USA). The mass spectra of the peptides were detected with a data-dependent 4-event scan method (a survey FT-MS parent scan followed by sequential datadependent FT-MS/MS scans on the three most abundant peptide ions from the parent scan). Proteins were identified from the mass spectra results with Proteome Discoverer software for protein database search using the International Protein Index (IPI) Human Protein Database (version 1.79). Quantification was conducted using SIEVE. Results: About 3000 proteins were detected in tears. Among those, 236 proteins (MW 7.4-466 kDa) were chosen as candidates for early diagnosis of the JIA-associated uveitis. Besides the rheumatoid factors RFET12, RF-IP14, RF-IP24, cytokines and T-cell receptor alpha-chain, we identified anti-CD40 single-chain antibody fragment A49, inhibiting protein CD40 which is a member of the TNF-receptor superfamily, lipocalin-1 precursor, associated with immune response and prostaglandin synthesis, clusterin inhibiting the cytolytic reaction of complement components, anti-TNF-alfa antibody light chain Fab fragment, protein phosphatase, regulatory subunit 15B, which plays a role in cell progression, apoptosis and regulation of membrane receptors and channels, DMBT/8kb.2 protein, which takes part in the interaction of tumor cells and the immune system. Conclusion: The result of our study demonstrates the benefits of high resolution mass- spectrometry for analysis and development of molecular signatures which can be used in diagnostics. Hierarchical clustering methodology allowed grouping according to expression profiles and the dendrogram construction procedure revealed clusters of proteins associated with iron metabolism as the most promising markers of JIA-associated uveitis. Earlier it was shown that induced anterior uveitis in the eyes of rats can be described in terms of proteins drawn from the anterior chamber (Sobn et al., 2000), which result is close to our terms of description. [ABSTRACT FROM AUTHOR]

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down's syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

Background: Systemic lupus erythematosus (SLE) is the most frequent and serious systemic connective tissue disease. Nowadays there is no clear guidance on its treatment in childhood. There are a lot of negative effects of standard-of-care treatment (SOCT), including steroid toxicity. Rituximab (RTX) is the biological B-lymphocyte-depleting agent suggested as a basic therapy in pediatric SLE., Aim: To compare the benefits of RTX above SOCT., Methods: The data from case histories of 79 children from the Saint-Petersburg State Pediatric Medical University from 2012 to 2022 years, were analyzed. The diagnosis of SLE was established with SLICC criteria. We compared the outcomes of treatment of SLE in children treated with and without RTX. Laboratory data, doses of glucocorticosteroids, disease activity measured with SELENA-SLEDAI, and organ damage were assessed at the time of initiation of therapy and one year later., Results: Patients, treated with RTX initially had a higher degree of disease activity with prevalence of central nervous system and kidney involvement, compared to patients with SOCT. One year later the disease characteristics became similar between groups with a more marked reduction of disease activity (SELENA-SLEDAI activity index) in the children who received RTX [-19 points (17; 23) since baseline] compared to children with SOCT [-10 (5; 15.5) points since baseline, P = 0.001], the number of patients with active lupus nephritis, and daily proteinuria. During RTX therapy, infectious diseases had three patients; one patient developed a bi-cytopenia., Conclusion: RTX can be considered as the option in the treatment of severe forms of SLE, due to its ability to arrest disease activity compared to SOCT., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Uveitis is the most frequent extra-articular manifestation of juvenile idiopathic arthritis (JIA). Our study is aimed to evaluate the possible difference in arthritis course depending on uveitis presence in patients with JIA, treated with biologics., Methods: From our database of patients with JIA treated with biologics, we extracted patients to whom the first agent was administrated with or without MTX. The exclusion criteria included treatment with current systemic corticosteroids, infliximab, rituximab, observation period <3 years, and no missing data. After selection, 175 patients were eligible for analysis. We evaluated clinically significant flare with joint involvement (which required change of biologic or non-biologic DMARD) and time to flare. We compared two groups: (i) patients with uveitis ( n = 32) and (ii) patients without uveitis ( n = 143). For statistical analysis, we used Cox's regression models, the log-Rank test, x 2 test, and the Mann-Whitney test., Results: There was no difference in gender distribution and achievement of arthritis remission between groups. Patients in the non-uveitis group predominantly received etanercept (64.3%). In the uveitis group, the most prescribed biologic agent was adalimumab (71.9%). The presence of uveitis increased the risk of JIA flare, OR = 3.8 (95% CI: 1.7; 8.7), and the cumulative probability of joint flare, RR = 4.5 (95% CI: 1.7; 12.1), p =.003, after adjustment on methotrexate, RR = 3.1 (1.6; 6.), p =.0008. In the subgroup of patients treated with adalimumab, the absence of methotrexate increased the cumulative probability of flare [RR = 6.5 (95% CI: 1.4; 31.1), p = 0.02]., Conclusion: The presence of uveitis proved to be a risk factor in JIA flare. Methotrexate can decrease the cumulative flare probability. Further trials are required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kostik, Gaidar, Sorokina, Avrusin, Nikitina, Isupova, Chikova, Korin, Orlova, Snegireva, Masalova, Dubko, Kalashnikova and Chasnyk.)

JAK-inhibitors are small molecules blocking the JAK-STAT pathway that have proven effective in the treatment of different immune-mediated diseases in adults and juvenile idiopathic arthritis (JIA)., Aim of Study: To evaluate the safety and efficacy of tofacitinib in children with different rheumatic diseases., Material and Methods: We extracted information from 24 children with the following diagnosis: JIA ( n = 15), undifferentiated systemic autoinflammatory diseases (SAIDs) ( n = 7), and juvenile dermatomyositis (JDM) ( n = 2) who have been treated with tofacitinib for a period of longer than 6 months. The treatment outcomes were classified according to the opinion of the attending physicians as having a complete response (CR), i.e., the absence of disease activity, or a partial response (PR)-a significant improvement of symptoms and disease activity, or no response (NR)-no changes in disease activity., Results: CR was achieved in 10/24 patients; 7/15 among JIA patients, 1/2 among JDM patients, 4/7 among SAID patients, and PR in 5/15 of JIA, 1/2 of JDM, and 3/7 of SAID patients. Three non-responders with JIA discontinued tofacitinib. Corticosteroids were successfully tapered off in 11/14 patients and discontinued in 2/14 patients. Four patients had side effects not requiring treatment discontinuation: liver enzyme elevation ( n = 2), hypercholesterolemia ( n = 1), lymphadenitis ( n = 1)., Conclusion: JAK-inhibitors are effective new therapies for the treatment of multiple immune-mediated diseases. Our experience has shown the best results in patients with JIA and JIA-associated alopecia, and type I interferonopathies. More data from randomized controlled clinical trials are needed to use JAK-inhibitors safely in pediatric rheumatic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kostik, Raupov, Suspitsin, Isupova, Gaidar, Gabrusskaya, Kaneva, Snegireva, Likhacheva, Miulkidzhan, Kosmin, Tumakova, Masalova, Dubko, Kalashnikova, Aksentijevich and Chasnyk.)

Objectives: To re-evaluate the ability of methotrexate (MTX) to prevent the onset of uveitis in Russian children with juvenile idiopathic arthritis (JIA)., Methods: The clinical charts for all consecutive patients who received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except NSAID) and patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were excluded. Each patient was examined after at least a 2-year follow-up period after the first visit to establish whether uveitis had occurred., Results: A total of 281 patients with a median disease duration of 3.8 years were included. 191 patients (68%) were treated with MTX. During the observation period, 64 patients (22.8%) developed uveitis, a median of 1.6 year after disease onset. The frequency of uveitis was lower in MTX-treated than in MTX-untreated patients (11.5% vs. 46.7%, respectively, OR=6.7 (95%CI:3.7-12.3), p=0.0000001). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis (HR=4.35, p=0.000001). In subgroup analysis it was shown that MTX was more preventive in boys than in girls, and in patients with JIA onset age of over 5 years compared to those with disease onset less than 5 years. The data of survival analysis of MTX prevention has shown that benefits do not depend on the number of active joints and ANA status., Conclusions: MTX therapy may prevent the onset of uveitis in children with JIA. Further randomised controlled trials are required to confirm our results.