Background:Early-onset form of systemic juvenile idiopathic arthritis (sJIA) often presents severe disease course. Choosing the optimal therapy option as first-line treatment is necessary for rapid improvement of patients’ quality of live and prevention of further radiologic progression.Objectives:To evaluate the long-term effectiveness and safety of tociliizumab (TOC) in sJIA patients depending on the duration of the disease treated in the National Medical Research Center of Children`s health, Moscow, Russia.Methods:The study was conducted as a subanalysis of the prospective cohort study to evaluate the efficacy of biologics in children with sJIA. Analysis included sJIA patients younger than 4 years of age at the moment of TOC initiation. Patients were divided into 2 groups: with disease duration shorter than 6 month (ShorterDD group, n=35) and more than 6 month (LongerDD group, n= 19). 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. Treatment safety was evaluated according to the data presented in the Adverse Event Reports.Results:TOC was first biologics in 34/35 (97.1%) patients in ShorterDD group and 18/19 (94.7%) patients in LongerDD group. Groups were comparable in terms of disease activity at TOC initiation with 100% of patients presented active systemic features. 31/35 (88.6%) patients in ShorterDD group and 17/19 (89.5%) patients in LongerDD group have median 3 (IQR 1: 6) and 5 (IQR 3: 7.5) active joints, respectively (p=0.119). JADAS-71 level was 17.14 ± 6.25 ShorterDD group and 17.36 ± 5.45 in LongerDD group (p=0.895).TOC showed high efficacy after first months of treatment with only 6/35 (17.1%) patients in ShorterDD group and 7/19 (36.8%) in LongerDD group remained with active systemic features (p=0.181). JADAS-71 level decreased to 0 points 26/35 patients (74.3%) in ShorterDD group and in 11/19 patients (57.9%) LongerDD group (p=0.237). After 3 month of treatment, WID was achieved by 27/35 patients (77.1%) in ShorterDD group and by 9/19 patients (47.4%) LongerDD group (p=0.038). ACR Pedi 50/70/90 was achieved by 88.6%/85.7%/80% of patients in ShorterDD group and by 84.2%/73.7%/68.4% of patients in LongerDD group after 1 months of treatment and in 77.1%/74.3%/74.3% and 84.2%/78.9%/68.4%, respectively, after 3 months of treatment.Conclusion:Initiation of tocilizumab treatment in sJIA patients under 4 years of age is highly effective. However, early treatment within first 6 month after disease onset had advantages in speed of reaching an inactive disease as soon as after 3 months of therapy.Disclosure of Interests:Elizaveta Krekhova: 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, Meyri Shingarova: None declared, Alina Alshevskaya: None declared, Andrey Moskalev: None declared, Ivan Kriulin: None declared
Background Patients with systemic juvenile idiopathic arthritis (sJIA) may not respond sufficiently to tocilizumab and rituximab therapy. Some patients reached remission of systemic features but had persistent arthritis. In these cases switching to TNFα ingibitor might be beneficial. Objectives To evaluate efficacy and safety of TNF blockers in the treatment of sJIA refractory to DMARDS, rituximab or tocilizumab. Methods Patients fulfilling the ILAR classification criteria for sJIA (n=14, boys 5) who were switched from rituximab (n=9) or tocilizumab (n=5) to TNF blockers (adalimumab n=10, etanercept n=4) were enrolled in a prospective observational study conducted in one Russian pediatric center. Patients received concominant therapy: methotrexate (n=2), methotrexate and cyclosporine (n=12), prednisolone (n=1). The mean age was 9,1 (8; 14,9) (here and after Me (25;75)), the mean age at disease onset - 2,1 (1;4,5) years, mean disease duration - 7 (4; 10)years, the remission of systemic features - 2,2 (range from 1 to 5 years). Because of persistent arthritis without systemic manifestations antiTNF therapy were initiated after 2,4 years rituximab and 1,4 years tocilizumab treatment. The efficacy was evaluated according to the ACR30/50/70/90 paediatric criteria and criteria of remission. The duration of TNFblockers therapy and observation was 2 months (n=14), 6 m (n=11), 12 m (n=7) and 24 m (n=5). Results The ACR30/50/70/90 improvements were reached by 95/64/50/28% of patients at month 2, by 100/82/73/73% of patients at month 6, by 100/100/86/86% of patients at month 12. The inactive disease was registrated at 54% (6/11) patients in 6 months, inactive disease and remission was registrated at 86% (6/7) patients in 12 months, at 100% (5/5) patients in 24 months. Nobody had flare of systemic manifestations. The number of AE decreased from 4,6 to 2,6 per 100 patients year (p,0.05) versus rituximab or tocilizumab treatment and antiTNF therapy. Conclusions AntiTNF therapy may be perspective in patients with sJIA with remission of systemic features and active arthritis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1934
BackgroundProlonged therapy with biological agents (BAs) may cause adverse events, which leads to the necessity of discontinuation of BAs in patients with juvenile idiopathic arthritis (JIA), once complete disease quiescence has been achieved.ObjectivesTo estimate the length of time in clinical remission and time to disease flare after discontinuation of treatment with BAs.Methods83 patients with JIA (33 – with systemic onset, 50 – with oligo- or polyarticular arthritis) were included in the survey. The cohort was 34,9% (29 patients) male and 65,1% (54 patients) female with a mean age of 11±3,69 years (range 5–17 years). All patients with systemic JIA (sJIA) were treated with tocilizumab, 35 (70%) patients with other types of JIA received etanercept, 15 (30%) – adalimumab. 14 (42,4%) patients with sJIA additionally got methotrexate, 5 (15,1%) – cyclosporine, 5 (15,1%) – glucocorticoids, 1 (3,0%) – leflunomide; 9 (25,7%) and 7 (46,6%) patients took combination therapy of etanercept or adalimumab and methotrexate. Patients were randomized into 2 main groups using envelope method: in a first group a BA was discontinued abruptly, while in the second it was tapered gradually by increasing injection/infusion interval.ResultsDuration of inactive disease/clinical remission during tocilizumab treatment was 43±12,16/37±12,16 months, etanercept – 40±13,13/34±13,17 months, adalimumab – 48±11,9/40±12,06 months. Tocilizumab, etanercept, adalimumab were discontinued in 22 (66,6%), 28 (80,0%), 11 (73,3%) patients and were tapered by increasing injection/infusion interval in 11 (33,4%), 7 (20,0%), 4 (26,7%) cases, respectively. After withdrawal of tocilizumab, etanercept and adalimumab 29 (87,9%), 24 (68,6%), 6 (40,0%) patients remained in remission of JIA for 6±10,23 (1–48) months, 6±5,07 (1–20) months and 6±13,33 (4–38) months, respectively. 4 (12,1%), 11 (31,4%), 9 (60,0%) patients flared within 8±5,65 (6–18) months, 5,5±3,49 (1,5–12) months and 4±4,64 (1–13) months after discontinuation of tocilizumab, etanercept and adalimumab, respectively.ConclusionsWithdrawal of BAs after clinical remission for more than 1,5 years was not associated with a disease exacerbation in more than 70% of patients with JIA. A mean duration of clinical remission after withdrawal of BAs was 6 months.Disclosure of InterestE. Kashchenko Grant/research support from: Novartis, E. Alexeeva Grant/research support from: Roche, Abbott, Pfizer, Bristol-Myers Squibb, Centocor, Novartis, Speakers bureau: Roche, Merck Sharp & Dohme, Abbott, Bristol-Myers Squibb, Medac, Novartis, Pfizer, T. Bzarova Grant/research support from: Roche, Pfizer, Novartis, Speakers bureau: Roche, Merck Sharp & Dohme, Abbott, Pfizer, S. Valieva Grant/research support from: Roche, Bristol-Myers Squibb, Speakers bureau: Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Medac, Novartis, K. Isaeva Grant/research support from: Roche, Novartis, R. Denisova Grant/research support from: Roche, Centocor, Novartis, Speakers bureau: Roche, Merck Sharp & Dohme, Abbott, Medac, O. Lomakina: None dec...
BackgroundMacrophage activation syndrome (MAS) is a severe hyperinflammatory response that develops against the background of juvenile idiopathic arthritis (JIA). It is known that the clinical feature of MAS on biologic therapy has other clinical manifestations, different from biologically naive patients.ObjectivesTo study the clinical and laboratory features of macrophage activation syndrome in patients with juvenile idiopathic arthritis with systemic onset (sJIA) on the biologic therapy.MethodsThe study included 100 patients with MAS (114 cases of MAS) who observed in the rheumatological department of the National Medical Research Center for Children’s health of Ministry of health. All patients met the criteria for the diagnosis of sJIA and MAS. There were children in our study who did not receive biologic therapy – 84 (74%) cases, and children who had MAS in the biologic therapy – 30 cases (26%). The drugs are distributed as follows: tocilizumab - 7 cases (6%), kanakinumab - 20 cases (17%), etanercept – 2 cases (2%), adalimumab – 1 case (1%). For pairwise intergroup comparisons of quantitative variables, the nonparametric Mann-Whitney test was used.ResultsIn comparative analysis of biologic-naive and on biologic patients, the greatest differences were obtained for the following clinical manifestations: rash, lymphadenopathy, myalgia (p<0.05). Fever was the most common symptom in both groups and was present in almost all patients (99%). All patients had elevated level of ferritin in the blood serum (773 ng/ml to 130149 ng/ml). Laboratory picture of MAS in the group of on biologic patients differed significantly from the group of patients naive for biologic therapy (Table 1). The most significant differences were found among the following laboratory parameters: hemoglobin level, the number of erythrocytes and platelets, erythrocyte sedimentation rate (ESR), levels of C-raective protein (CRP), ferritin, lactatedehydrogenase (LDH), albumin.Table 1.Laboratory data of patients with MAS.nReference valuesMedianMinimumMaximumMann-Whitney Criterion (p)Biologic-naive cases of MAS(n= 84)Hemoglobin, g/l84120-14596,5061,00145,000,008Red blood cells, 1012/l844,5-5,33,782,135,010,001Platelets, 109/l84150-440149,0041,00523,000,025White blood cells, 109/l844,5-11,54,420,6925,840,074ESR, mm/h842-2045,002,00111,000,001CRP, mg/l840-5111,567,54368,310,006Ferritin, ng/ml8414-1244195,21702,38130149,200,022LDH, U/l8491-295413,50162,005245,000,059Albumin, g/l8438-5429,0016,1063,000,001On biologic cases of MAS(n = 30)Hemoglobin, g/l30120-145104,5067,00163,000,008Red blood cells, 1012/l304,5-5,34,173,106,150,001Platelets, 109/l30150-440101,504,00362,000,025White blood cells, 109/l304,5-11,53,220,7015,580,074ESR, mm/h302-2017,502,0098,000,001CRP, mg/l300-555,771,86407,120,006Ferritin, ng/ml3014-1242319,59773,90121396,000,022LDH, U/l3091-295600,0010,602148,570,059Albumin, g/l3038-5432,8020,3051,900,001ConclusionOn biologic patients may also develop MAS, which is often difficult to diagnose due to the poor clinical picture and low laboratory activity. In this case, hyperferritinemia remains as a highly specific marker of MAS.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: 26461152Disclosure of InterestsIvan Kriulin Speakers bureau: Speaker for Novartis., Ekaterina Alexeeva Speakers bureau: Speaker for Roche, AbbVie, Bristol-Myers, Squibb, MSD, Novartis and Pfizer., Grant/research support from: Financial grants from Roche, Pfizer, Centocor, Eli Lilly, AbbVie, Bristol-Myers Squibb, MSD, Sanofi, Amgen and Novartis., Tatyana Dvoryakovskaya Speakers bureau: Speaker for Roche, AbbVie, Bristol-Myers, Squibb, MSD, Novartis and Pfizer., Grant/research support from: Financial grants from Roche, Pfizer, Centocor, Eli Lilly, AbbVie, Bristol-Myers Squibb, MSD, Sanofi, Amgen and Novartis., Rina Denisova Speakers bureau: Speaker for Roche, AbbVie, MSD, Novartis., Grant/research support from: Financial grants from Roche, Pfizer, Centocor, Sanofi and Novartis., Ksenia Isaeva Grant/research support from: Financial grants from Roche, Novartis and Sanofi., Aleksandra Chomakhidze: None declared, Anna Mamutova Speakers bureau: Speaker for Novartis., Grant/research support from: Financial grants from Eli Lilly., Olga Lomakina Grant/research support from: Financial grants from Pfizer, Eli Lilly., Anna Fetisova Grant/research support from: Financial grants from Amgen., Marina Gautier: None declared, Kristina Chibisova: None declared, Elizaveta Krekhova Speakers bureau: Speaker for Novartis., Irina Tsulukiya: None declared
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