Background. Immunological potency of 13-valent pneumococcal vaccine (PCV-13) in children with systemic juvenile idiopathic arthritis (SJIA) is still unstudied. Estimates of the genetically engineered biologic drugs (GEBD) effects on pneumococcal vaccination results also remain controversial.Objective. The aim of the study was to explore the PCV-13 efficacy in patients with SJIA and who is on treatment with monoclonal antibodies against interleukin 6 receptor (tocilizumab) and interleukin 8 receptor beta (canakinumab).Methods. The study included patients under the age of 18 with SJIA in remission or active form of disease vaccinated with PCV-13. The vaccine was administered in single dose of 0.5 ml intramuscularly in patients on treatment with GEBD or 3 weeks before GEBD administration for the first time (for patients with active disease). Vaccination was considered effective at achievement of the minimum protective level of antibodies to capsular polysaccharide of pneumococcus (anti-SPP IgG; ≥ 7 U/ml) or increase of anti-SPP IgG level ≥ 2 times in 4 weeks after vaccination. The anti-SPP IgG levels were measured with enzyme immunoassay.Results. The study included 53 patients (27 girls) in remission of SJIA and 25 (16 girls) in active disease. Median age was 13.3 and 10.8 years respectively. Tocilizumab/canakinumab was administrated in 43/10 and 18/7 patients respectively. Minimum significant anti-SPP IgG level and two-fold increase in anti-SPP IgG level were recorded in 49/53 (92%) and 32/53 (60%) patients with SJIA in remission, as well as in 22/25 (88%) and 18/25 (72%) patients in active disease respectively. PCV-13 immunological potency in patients with SJIA in remission and in active disease (in those who were initially administrated and who did not receive GEBD) did not differ.Conclusion. PCV-13 vaccination allows to achieve protective antibodies level in most of the patients with SJIA in children population regardless of the disease stage and the history of GEBD administration.

BackgroundA significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (bDMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required.MethodsPatients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the paediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS-71 = 0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up from time first canakinumab dose administered was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from electronic outpatient medical records.ResultsDuring the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at baseline was 8.2 [interquartile range (IQR) 4.0–12.9] years, with the median sJIA duration being 1.8 (IQR 0.8–5.8) years; 37 (80%) patients received at least one conventional DMARD (cDMARD; oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (IQR 282–404) days. During the follow-up, 1 patient discontinued canakinumab due to tuberculosis detection and the dose was reduced or the injection interval increased in 4 (9%) patients. In total, 27 (60%) patients continued to receive at least one cDMARD. Improvement according to the ACR30 criteria was achieved in 43 patients [96%; 95% confidence interval (CI) 85–99], inactive disease in 42 (93%; 95%CI 82–98), and remission in 37 (82%; 95% CI 69-91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 AEs (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases.ConclusionsOne-year canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA.

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

Background:Macrophage activation syndrome (MAS) is a life-threatening complication of systemic-onset juvenile idiopathic arthritis (sJIA) characterized by fever, hepatosplenomegaly, lymphadenopathy, coagulopathy, and rapid development of multiple organ failure. MAS is triggered by viral and bacterial infections, most often Epstein-Barr viruses, cytomegalovirus, influenza and parainfluenza viruses, parvavirus B19, yersiniosis, salmonellosis, sepsis.Despite modern diagnostic and treatment technologies, MAS still remains a formidable complication of sJIA, it is characterized by an aggressive course, a heterogeneous clinical presentation, especially in conditions of treatment with genetically engineered biological drugs, an ambiguous response to pathogenetic therapy and is accompanied by mortality in 5-10% of patients.Objectives:To analyze the clinical and laboratory features of MAS in children with sJIA and to study the genetic predisposition of this syndrome.Methods:The study included 24 patients with MAS who are being followed up in the rheumatology department of the National Medical Research Center of Children’s Health, Moscow. The clinical presentation and laboratory manifestations were assessed in 24, and genetic features were described in 7 patients using a new generation sequencing with further biostatistical processing of the obtained genetic data.Results:Of 24 patients, 23 (98%) had fever, 16 (68%) patients had rash, 17 (72%) - organomegaly, 4 (16%) - polyserositis, 2 (7%) - myalgia and myopathy. All 24 (100%) patients had an increase in ferritin level of more than 684 ng/ml, 98% of them had a high level of lactate dehydrogenase (LDH) and 97% - a high level of triglycerides. In CBC, cytopenia was found in 80% of children: in 54% - erythrocytopenia, in 74% - leukopenia, in 88% - thrombocytopenia, in 15% - sharp decrease in erythrocyte sedimentation rate. In a coagulogram of 24 patients, 90% had an increase in D-dimer, 85% had a decrease in fibrinogen. Hyponatremia presented in 95% of patients. Thus, 85% of patients met the diagnostic criteria of the HLH-2004 protocol, adapted for children with sJIA. Genetic characteristics were analyzed in 7 children out of 94 patients with MAS. They are presented in Table 1. These patients have rare and frequent variants, as well as genes polymorphisms that are associated with macrophage activation syndrome.Table 1.The number of genetic variants in children with MAS (n=7).GenePatient № 1Patient №2Patient № 3Patient № 4Patient №5Patient №6Patient №7LYST02473464NLRC44444463NLRP12510644124NLRP31855575TNFAIP32220222UNC13D182510182618XIAP1100131Conclusion:The macrophage activation syndrome has a typical clinical presentation, there are clinical and laboratory manifestations: fever, hyperferritinemia, cytopenia, hyponatremia, increased levels of LDH and triglycerides, based on which, a diagnosis can be made. Patients with MAS at our center also had genetic characteristics that predisposed to the development of this condition.References:[1]Crayne CB, Albeituni S, Nichols KE, Cron RQ. The Immunology of Macrophage Activation Syndrome. Front Immunol. 2019 Feb 1;10:119. doi: 10.3389/fimmu.2019.00119. PMID: 30774631; PMCID: PMC6367262.[2]Henderson LA, Cron RQ. Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management. Paediatr Drugs. 2020 Feb;22(1):29-44. doi: 10.1007/s40272-019-00367-1. PMID: 31732958; PMCID: PMC7334831.[3]Ravelli A, Davì S, Minoia F, Martini A, Cron RQ. Macrophage Activation Syndrome. Hematol Oncol Clin North Am. 2015 Oct;29(5):927-41. doi: 10.1016/j.hoc.2015.06.010. Epub 2015 Aug 25. PMID: 26461152.Disclosure of Interests:None declared

Background:Familial Mediterranean fever (FMF) is a monogenic autoinflammatory hereditary disease characterized by recurrent episodes of fever with sterile peritonitis, pleural inflammation, arthritis, and/or erysipelas-like rash. Among all variants of the MEFV gene, according to the literature, five pathogenic ones have been identified, which in 75% of cases lead to the development of a typical clinical presentation: V726A, M694V, M694I, M680I, and E148Q. Among them, the M694V variant is the most common and occurs in patients with FMF in 20-65% of cases. At the same time, approximately 10 to 20% of patients meeting the diagnostic criteria for FMF do not have pathogenic variants in the MEFV gene. Despite the fact that the molecular genetic, pathogenetic and clinical features of the disease have been studied detailed, the diagnosis remains difficult due to the lack of a clear correlation between the patient’s clinical and genetic data.Objectives:To analyze the obtained genetic data of patients with pathogenic variants in the MEFV gene.Methods:The study included 103 patients who are mainly observed at the rheumatology department of the National Medical Research Center of Children’s Health of Ministry of Health of the Russian Federation in Moscow. All patients underwent analysis of the MEFV gene using Sanger sequencing with further statistical processing of the data obtained.Results:Of 103 patients, the pathogenic variant of the MEFV gene was found in 93 patients (90.3%), in 10 patients (9.7%) - the pathogenicity of the revealed variant was contradictory. Of 93 patients with the pathogenic variant of MEFV, the clinical presentation of the disease fits to FMF in 37 patients (39.6%). 11 (29.7%) of them had a mutation in M694V. Out of 37 children who met the criteria for FMF diagnosis, 15 (40.5%) children had a homozygous pathogenic variant of MEVF, and 22 (59.5%) children had two mutations in a heterozygous state. 57 patients who do not have a typical clinical presentation, which is specifical for FMF are observed at the departments of rheumatology, cardiology and nephrology, 13 patients are on an outpatient observation, and 6 patients at the time of the study are over 18 years old. 8 (14%) of them had a mutation in M694V. Among 57 patients with pathogenic heterozygous variants in a, 22 patients (38.6%) are observed in the rheumatology department, among them:• Enthesitis-related arthritis - 2 patients (9%);• Systemic juvenile arthritis - 13 patients (59%);• Oligoarthritis - 5 patients (23%);• Polyarthritis- 2 patients (9%).Conclusion:Analysis of the obtained data showed that FMF is characterized by a combination of the clinical presentation and the pathogenic variant in the MEFV gene. However, the disease manifests itself not only in the homozygous pathogenic variant, but also in the combination of two mutations in heterozygous. The presence of one heterozygous mutation, generally, does not lead to the development of FMF.References:[1]Konstantopoulos, A. Kanta, C. Deltas, V. Atamian, D. Mavrogianni, A.G. Tzioufas, I. Kollainis, K. Ritis, H.M. Moutsopoulos, Familial Mediterranean fever associated pyrin mutations in Greece Ann. Rheum. Dis., 62 (2003), pp. 479-481, 10.1136/ard.62.5.479.[2]Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with Mediterranean Fever,Seminars in Arthritis and Rheumatism,Volume 43, Issue 3, 2013, Pages 387-391familial Mediterranean fever. Arthritis Rheum 2003; 48: 1149–1155.[3]Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60:185.Disclosure of Interests:None declared