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Background:The efficacy of tocilizumab for treatment patients with systemic juvenile idiopathic arthritis (sJIA) was demonstrated before. We want to describe tocilizumab drug survival based on data from a single-center observation.Objectives:To analyze the drug survival of tocilizumab in patients with sJIA treated at the National Medical Research Center of Children`s health, Moscow, Russia.Methods:Medical records from sJIA patients treated with tocilizumab (TOC) were analyzed retrospectively from the National Medical Research Center of Children`s health, Moscow, Russia.Results:One hundred ninety-two patients presenting with sJIA were included in this observation, with a median age at treatment initiation of 7,2 (interquartile range, IQR 3,9-10,8) years and a median disease duration of 1,9 (IQR 0,4-5,9) years. All patients had been bio-naive. TOC therapy was highly effective in patients with sJIA. At 6 month of follow-up 148/172 (86%) patients achieved inactive disease according the criteria C. Wallace, disease activity persisted in 24/172 (14%) patients. At 1 year of medication 139/150 (92%) patients had inactive disease. We analyzed the reason of TOC withdrawal retrospectively. A total of 82/192 drug withdrawals were performed. TOC was discontinued due to primary ineffectiveness in 4 patients, due to secondary ineffectiveness in 39 patients. 33 patients achieved drug-free remission. Six patients developed side effects that required discontinuation of TOC therapy (4 patients had allergic reactions, 1 patient developed tuberculosis, 1 patient had severe neutropenia). 47/82 patients were switched on other biologic drug: on canakinumab (31), on TNF-inhibitors (11), on rituximab (5). In summary, TOC was canceled in 49/192 (25%) patients due to ineffectiveness or AEs in our cohort.Conclusion:These results demonstrated that TOC is highly effective as the first biologic drug in patients with sJIA. Our observations have shown a good tolerability and survival of the IL-6 inhibitor TOC in patients with sJIA treated in a real-world clinical setting.Disclosure of Interests:None declared

Juvenile idiopathic arthritis (JIA) is the most common and prevalent rheumatic disease in childhood which is based on a chronic autoimmune inflammation. Inactive disease and remission are now the primary treatment goal in JIA and biologics have been playing an important role to reach this objective. The biologics of the first choice for the treatment of non-systemic JIA are the Tumor Necrosis Factor - alpha (TNFα) inhibitors; on this therapy patients can achieve clinically inactive disease and long-term remission. Currently, little is known about when or how to stop TNFα inhibitors, when a good clinical response is achieved, and therefore no guidelines are available. To estimate the length of clinical remission after discontinuation of treatment with TNFα inhibitors in patients with non-systemic juvenile idiopathic arthritis. A total of 393 patients with JIA who were treated with TNFα inhibitors at the Rheumatology Department of the National Medical Research Center of Children's Health (Moscow, Russia) were screened for inclusion in this retrospective study. Patients were treated with etanercept 1 times a week, 0.8 mg per kg of body weight per dose, with adalimumab 24 mg/m2 body surface area administered every other week until the end of therapy.Treatment was terminated abruptly. Inactive disease was defined according to the preliminary criteria of Wallace et al.[1] 77 patients (27—male, 50—female) with a mean age at diagnosis of 4 years (range 1–18 years) were included in the analysis. Of those, 69 of them discontinued TNFα inhibitors due to a long-term remission on treatment, 8 patients as a result of side effects, and there were excluded from our study.: allergic reaction (n = 5), development of uveitis (n = 1), alopecia (n = 1), recurrent infection (n=11).The clinical subtypes of JIA were RF-negative polyarticular JIA -28 (40,58%) oligoarthritis—38 (55,07%), enthesitis-related arthritis—3 (4,35%). TNFα inhibitors were started after a mean 46,43 (range 1–144) months of disease. The mean duration of therapy with TNFα inhibitors were 46,63 (range 10-113) months, with a mean duration of remission on medication 40,63 (range 6-107) months before withdrawal of TNFα inhibitors. 40/69 (57,97 %) patients did not develop a disease exacerbation and remained in long-term remission off medication—more than 24 months. Early flares, that is less than 6 months after termination of TNFα inhibitors, were observed in 4/69 (5,8%) patients. 29 (42,03%) patients restarted TNFα inhibitors after exacerbation, due to lack of improvement after no biological DMARDs. All patients in whom TNFα inhibitors were reinitiated responded satisfactorily. Among patients with JIA in whom TNFα inhibitors were discontinued after inactive disease was achieved, 57,97 % had disease in clinical remission more than 24 months after stopping anti-TNFα therapy. No association was observed between the duration of inactive disease prior to TNFα inhibitors cessation and the time to disease relapse. In addition, we also ob- served no correlation between the risk of flare and the length of anti-TNF α therapy after inactive disease was achieved. In our population, TNFα antagonists were withdrawn a median of 38 (4-107) months after inactive disease was achieved. Data from our experience with anti-TNF α agents in the treatment of JIA suggest that 57,97 % of patients can be successfully withdrawn from TNF α antagonists for at least 24 months. [1]Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, for the Childhood Arthritis and Rheumatology Research Alliance (CARRA), the Pediatric Rheumatology Collaborative Study Group (PRCSG), and the Paediatric Rheumatology Interna- tional Trials Organisation (PRINTO). American College of Rheumatology provisional criteria for defining clinical in- active disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:929–36. None declared.

The safety of vaccination of children with rheumatic diseases is determined not only by the risk of adverse events but also by the risk of exacerbation of the disease. The simultaneous administration of several vaccines can increase the likelihood of these events. To evaluate the clinical and laboratory signs of disease activity in children with juvenile idiopathic arthritis (JIA) after simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) infections. We included hospitalized patients with JIA ages 2 through 18 without serious comorbidity, immunized with polysaccharide conjugate vaccines against pneumococcal (PCV13) and Hib infections. Vaccines were administered (0.5 ml each) concurrently subcutaneously into the deltoid area. In all children before and 3 weeks after vaccination, clinical (joints with active arthritis, uveitis activity) and laboratory signs (increased ESR, concentrations of highly sensitive C-reactive protein – hsCRP, and calprotectin) of JIA activity were assessed. Serum hsCRP and calprotectin were quantified by ELISA. The upper limit of the reference interval for hsCRP was considered (according to the manufacturer's instructions) a value of 8.2 mg/L, for calprotectin – 2.9 μg/ml, and for ESR – > 10 mm/h. The study included 430 patients with JIA (girls 60.9%), median (IQR) age – 11.1 years (7.3 to 14.4), onset of JIA – 4.7 years (2.4 to 8.6). Patients with persistent oligoarticular JIA numbered 149 (34.7%), polyarticular RF-negative – 148 (34.4%), systemic – 101 (23.4%), enthesitis-related – 20 (4.7%), and polyarticular RF-positive JIA – 12 (2.8%). Biologic disease-modifying antirheumatic drugs (DMARDs) were administered to 278 (64.7%), non-biologic DMARDs (mostly methotrexate) – 282 (65.6%), corticosteroids – 45 (10.5%), and NSAIDs – 18 (4.2%) patients. Three weeks after vaccination, out of 100 (23.3%) patients with initially active joints, signs of active arthritis remained in 96 patients, of which 16 patients had a decrease in the median (IQR) number of active joints by 4 (2 to 8). Among patients without active joints at baseline, signs of active arthritis were not subsequently detected. Before vaccination, 9 patients had uveitis in the exacerbation phase, 7 - in the subactive phase, and 41 - in the remission phase. After vaccination, exacerbation of uveitis persisted in 4 patients. There were no new cases of uveitis or its exacerbation. The dynamics of laboratory signs of JIA activity are presented in Table 1. Initially, the high concentration of calprotectin was found in 191 (44.4%) patients, and after vaccination – in 220 (51.2%) patients; the difference was 6.7% (95% CI 1.0 - 12.5); hsCRP - in 34 (7.9%) and 51 (11.9%) patients; the difference was 4.0% (95% CI 0.6 - 7.3); high ESR – in 76 (17.7%) and 41 (9.5%) patients; the difference was -8.1% (95% CI -11.6 to -4.7), respectively. An independent predictor of new cases of high concentration of hsCRP (n = 36), but not new cases of high concentration of calprotectin (n = 94), was the initial number of joints with active arthritis – odds ratio 2.37 (95% CI 1.14 - 4.93). Simultaneous vaccination against pneumococcal (PCV13) and Hib-infections in children with JIA produced no negative dynamics of the traditional indicators of disease activity (joint activity, uveitis, high ESR). At the same time, 3 weeks after vaccination, an increase in the concentration of calprotectin and hsCRP was found in a small number of patients (<10%). None declared Table 1Laboratory signs of JIA activity after simultaneous administration of vaccines against pneumococcal (PCV13) and Hib-infectionsVariablesBaselineAfter 3 weeksRatio*p**Geometric mean (95% CI)Calprotectin, μg/ml2.93 (2.70 – 3.17)3.15 (2.92 – 3.40)1.08 (0.99 – 1.17)0.087hsCRP, mg/L0.69 (0.60 – 0.78)0.79 (0.69 – 0.90)1.15 (0.99 – 1.33)0.073ESR, mm/h4.4 (4.0 – 4.8)3.7 (3.4 – 4.0)0.84 (0.78 – 0.90)0.001Note. CI – confidence interval. * Ratios of paired observations (95% CI). ** P-value calculated in paired samples t-test.

Background:Anti-IL-17A biologic drug secukinumab (SEC) proved to be effective for treatment of psoriatic arthritis. However data about its efficacy in juvenile idiopathic arthritis (JIA) are restricted to off-label experience.Objectives:To evaluate the effectiveness and safety of SEC in JIA patients in the National Medical Research Center of Children`s health, Moscow, Russia.Methods:25 patients started SEC therapy from 12/2017 to 11/2019 in single-center prospective study. 3 patients withdrew treatment: two patients (8%) due to AE (1 - allergy followed by MAS after first injection and 1 – leukopenia) and one patient (4%) – after 10 months of treatment due to secondary inefficacy. Among others, 14 patients which were successfully treated for 6 months or longer were included into analysis. At the baseline, information was collected on the characteristics of the onset of the disease, previous therapy and its success. Patients were monitored at least 1 time per year. At each visit, clinical and laboratory characteristics of JIA severity were assessed. Response to therapy was assessed using the ACRPedi 30/50/70/90 criteria, the C.Wallace criteria for inactive disease (WID) and clinical remission. AEs were assessed at each visit.Results:Among 14 patients received SEC for at least 6 months, 7 (50%) have enthesitis-related arthritis, one (7.1%) – persistent oligoarthritis, 4 (28.6%) – RF-negative polyarthritis, 2 (14.3%) – psoriatic arthritis. 6 patients (42.9%) were HLA-B27 positive. Median age of JIA onset was 8.8 (IQR 5:11), age at SEC initiation – 14 (9.9:16.1), disease duration before SEC start – 3.3 (2.7:5.8). 7 (50%) were biologics-naïve, 2 (14.3%) were previously treated with anti-TNF drug, 5 (35.7%) have 2 or more different biologics in anamnesis.SEC demonstrated high efficacy after the first injection resulting in JADAS-71 decreasing in all patients by median 4.3 (1.6:7.1) points and 7/7/5/2 patients (50%/50%/35.7%/14.3%) achieved ACR Pedi 30/50/70/90 response.After 6 months of treatment, WID was achieved by 7 (50%) patients, JADAS-71 decreased from baseline level 15.2 (12.7:20.5) to 0.8 (0:4.2) points, and 14/13/11/9 patients (100%/92.9%/78.6%/64.3%) achieved ACR Pedi 30/50/70/90 response. One patients who had active uveitis at SEC initiation remained with subactive uveitis; one patient with uveitis remission had not flare episodes during follow-up period. One patient (7.1%) had successfully treated evaluation of transaminases after 4-th injection.Conclusion:Secukinumab showed high effectiveness and safety in children with JIA and can be further used both as a first-line drug in JIA associated with HLA-B27, and as an alternative drug for the ineffectiveness of the standard treatment regimen with biologics. No serious adverse events were registered during follow-up period.Disclosure of Interests:Ivan Kriulin: None declared, Ekaterina Alexeeva Grant/research support from: Roche, Pfizer, Centocor, Novartis, Speakers bureau: Roche, Novartis, Pfizer., Tatyana Dvoryakovskaya: None declared, Ksenia Isaeva: None declared, Aleksandra Chomakhidze: None declared, Evgeniya Chistyakova: None declared, Olga Lomakina: None declared, Rina Denisova: None declared, Anna Mamutova: None declared, Anna Fetisova: None declared, Marina Gautier: None declared, Dariya Vankova: None declared, Elizaveta Krekhova: None declared, Meyri Shingarova: None declared, Alina Alshevskaya: None declared, Andrey Moskalev: None declared

BackgroundDevelopment of biologics gives rise to novel classes of drugs, offering more options for treating children with primary or secondary failure of anti-TNF therapy. However, the question of whether or not previous exposure to biologic therapy and the number of previously administered biologics influence the efficacy of current treatment still needs to be solved.ObjectivesTo compare tocilizumab efficacy in biologics-naïve and biologics-switched patients with JIA.MethodsComparative analysis involved patients who had initiated TOC treatment at the National Medical Research Centre of Children’s Health (Moscow) depending on previous history of biologics therapy. Treatment efficacy was evaluated according to the dynamics of clinical and laboratory signs using the ACRPedi criteria. The Wallace criteria were used to evaluate whether or not remission had been achieved.ResultsThirty-two patients were biologics-naïve and 43 patients switched to TOC were previously treated with ETA (n=10), ADA (n=34), certolizumab (n=2), and infliximab (n=1). Children in the biologics-naïve group differed from the switchers in a number of important baseline parameters: shorter disease duration (2.13 [1.25:5.34] and 7.42 [3:10.75] years, respectively; p<0.001) and lower arthritis severity indices (the number of joints affected, the CHAQ and JADAS scores). Therapy with TOC in children was found very effective. The CHAQ and JADAS disease activity scores, the CRP and ESR laboratory values, morning stiffness duration, and the VAS score (assessed by both patient and physician), and the number of affected joints (swollen or painful joints, joints with the limited range of motion and with active arthritis) significantly decreased after 4 week therapy in all patients (p<0.01). The percentages of biologics-naïve patients and switchers who achieved ACR90 after the first 12 months of therapy were 31.25% and 25.6%, respectively (p=0.613). A smaller percentage of children achieved stable remission: 4.65% of switchers and 6.25% of biologics-naïve patients (p>0.999).ConclusionsTocilizumab therapy is highly efficient both as the first and subsequent biologic agent. Children with history of therapy with at least one biologic agent have lower chances for achieving remission during the first 12 months of therapy. However, this difference is most likely caused by the longer and more severe arthritis course in children allocated to the group of biologics-switched patients compared to biologics-naïve ones. Further matched large-cohort study is needed to identify predictors of response to therapy.Disclosure of InterestE. Alexeeva: None declared, T. Dvoryakovskaya Grant/research support from: Roche, Pfizer, M. Soloshenko: None declared, R. Denisova: None declared, K. Isaeva: None declared, A. Mamutova: None declared, V. Gladkikh: None declared, A. Moskalev: None declared

BackgroundThe use of therapy with anti-cytokine biologicals in routine practice has significantly increased the percentage of children showing good response to therapy and reduced the time to achieve pharmacological remission. Nevertheless, the problem related to selecting the optimal drug for a certain patient still remains to be solved.ObjectivesThis study was aimed at identifying clinical and laboratory parameters associated with response to tocilizumab (TOC) treatment in patients with RF-negative polyarticular JIA.MethodsThe prospective study to assess TOC efficacy involved 55 patients with RF-negative polyarticular JIA aged 9.42 years (IQR 5.96–13.42), with females (85.5%) predominating was conducted at the National Medical Research Centre of Children’s Health (Moscow). Treatment efficacy was evaluated using the ACRPedi criteria; Wallace’s criteria were used to assess whether a patient had reached inactive disease or remission. The potential baseline characteristics associated with treatment response were identified using univariate and multivariate logistic regression analyses. Baseline factors included the clinical, laboratory, and anamnestic data.ResultsTOC therapy showed high efficacy in children with RF-negative polyarticular JIA: 81.8/67.3/47.3/23.6% of patients reached the ACR30/50/70/90 criteria for the end of follow-up, respectively. The median time of achieving at least 30% improvement from baseline (ACR30) was 1 months (IQR 1:3).Univariate analysis showed that earlier age at initiation of Tocilizumab therapy, higher physician’s global assessment score using the 100-point Visual Analogue Scale, and longer morning stiffness were the factors associated with reaching ACR90. Younger age at therapy initiation, greater number of swollen joints and joints with limited range of motion, and history of using fewer biologicals are the factors associated with reaching inactive disease and remission. However, multifactorial analysis showed that only earlier age at initiation of TOC therapy was a statistically significant factor associated with reaching the best response to therapy in all the models.ConclusionsEarlier initiation of TOC therapy is associated with higher chances for reaching ACR90 and pharmacological remission in patients with RF-negative polyarticular JIA. Further studies in larger cohorts are needed to identify the optimal age at therapy initiation.Disclosure of InterestE. Alexeeva: None declared, T. Dvoryakovskaya Grant/research support from: Roche, Pfizer, M. Soloshenko: None declared, R. Denisova: None declared, K. Isaeva: None declared, A. Mamutova: None declared, V. Gladkikh: None declared, A. Moskalev: None declared

BackgroundJuvenile idiopathic arthritis (JIA) is one of the most frequent and most disabling rheumatic diseases in children. Children with JIA receiving immunosuppressive and genetically engineered biologic drugs belong to the high-risk group for the development of bacterial and viral infections, including those administered by preventive vaccines.ObjectivesOur aim was to evaluate the tolerability of the pneumococcal 13-valent conjugate vaccine (PCV) in children with JIA.MethodsIn a prospective cohort study, 3 groups were formed: children with JIA in the remission phase on methotrexate or etanercept (group I), with JIA in the active phase prior to the appointment of methotrexate or etanercept (group II), control group (conditionally healthy children). 0.5 ml of the 13-valent PCV was administered once subcutaneously during therapy in patients in the remission phase or 3 weeks before the appointment of methotrexate or etanercept in patients in the active phase.ResultsAt this stage of work, the tolerability of the 13 PCV vaccine was evaluated in patients with JIA, without systemic manifestations. In our study, the post-vaccination period was asymptomatic in 58% of the children in Group I, 66% in children in Group II, and in 60% in the control group. Most often in the postvaccinal period, local reactions were noted, which were painful at the place of administration of the vaccine in 6% of the children in group I, 8% in group II, and 24% in the control group, respectively. Less developed oedema and hyperemia at the injection site – in 12% of children in group I, 6% in group II, in 8% of children in the control group. There was no significant difference in the incidence of local reactions to vaccination of 13 PKV in patients with JIA and in children of the control group. Analysis of the time of occurrence and duration of local and systemic reactions to vaccination of 13 PKV showed that the maximum severity of symptoms was noted in the first day, by the 2–3 day of observation, complaints and fever disappeared. The increase in local reactions was noted 2 days after immunisation, followed by extinction to 3–4 days of follow-up. There were no serious adverse events in the post-vaccination period.ConclusionsVaccination with the 13-valent PCV in children with JIA is safety and is not accompanied by the development of serious adverse events.Disclosure of InterestE. Alexeeva Grant/research support from: Roche, Pfizer, Centocor, Novartis, T. Dvoryakovskaya Grant/research support from: Roche, Pfizer, M. Soloshenko: None declared, R. Denisova: None declared, K. Isaeva: None declared, A. Mamutova: None declared, N. Mayansky: None declared, N. Tkachenko: None declared, I. Zubkova: None declared, T. Kaluzhnaya: None declared, A. Gayvoronskaya: None declared, M. Broeva: None declared, M. Fedoseenko: None declared