The role of serum cytokine level in the evaluation of the efficacy of tocilizumab for the treatment of systemic-onset juvenile idiopathic arthritis / 中华检验医学杂志

Objective@#To evaluate the value of serum cytokine level in the efficacy of tocilizumab for the treatment of systemic-onset juvenile idiopathic arthritis.@*Methods@#30 cases with SoJIA hospitalized in Capital Institute of Paediatrics from June 2016 to October 2018 were treated with Interleukin-6 receptor antagonist(tocilizumab) injection. Among them, 20 were males(67%) and 10 were females(33%). The age at diagnosis was between 0.84 to 13years. Whiteblood cell, C-reactive protein, erythrocyte sedimentation rate, serum interleukin(IL-6, IL-2R, IL-8, IL-10, IL-1β) and tumor necrosis factor-alpha levels were observed before treatment, after the 2nd week, after the 6th week and after the 22nd week.Mann-Whitney nonparametric test and Chi-square test were used to analyze the data of cytokines pre and after-treatment.@*Results@#All of the 30 cases had fever before medication. The fever disappeared in 28 cases after using tocilizumab. One case stopped using tocilizumab because of allergic reaction and one case stopped because of poor efficacy. Among 28 cases with normal body temperature after medication, the arthritis and rash manifestations were significantly improved. WBC, AESR and CRP were all lower than those before medication. Within these 28 cases, the serum IL-6 level was168.50(67.40-589.25) pg/mL pre-treatment, 107.50(28.03-281.50) pg/mL after the 2nd week. There was no statistical difference between them(Z=-1.754, P>0.05). The serum IL-6 level was 64.05 (19.90-130.75) pg/mL after the 6th week and 24.80 (3.45-95.40) pg/mL after the 22nd week. Compared with pre-treatment, they were all lower than pre-treatment levels(Z=-2.942,-3.334,P<0.01,<0.01).Serum IL-2R level was 740.50(510.00-1 161.00)U/mL after the 2nd week, 796.50 (534.00-1 008.00) U/mL after the 6th week and 688.00 (527.00-889.50) U/mL after the 22nd week. Compared with pre-treatment [1 322.50(812.00-1 659.00)U/mL], they were all lower than pre-treatment levels (Z=-2.818,-3.130,-3.466, P<0.01, <0.01, <0.01). Serum TNF-alpha level was 23.70 (20.30-41.23) pg/ml after the 2nd week, 26.75(16.83-47.03) pg/ml after the 6th week,18.60(13.10-34.90) pg/ml after the 22nd week. Compared with pre-treatment [26.50(20.55-37.43) pg/ml], there were no statistical difference between after and pre-treatment(Z=0,-0.560,-1.954,P>0.05,>0.05,>0.05). Serum IL-8 level was 200.85(95.43-364.00)pg/ml after the 2nd week, 194.50(50.75-433.00)pg/ml after the 6th week, 161.50 (38.98-308.00)pg/ml after the 22nd week. Compared with pre-treatment [96.20(59.75-371.75) pg/ml], there were no statistical difference between after and pre-treatment(Z=-0.86,-0.131,-0.186,P>0.05,>0.05,>0.05). There was no statistical difference between after the 2nd week and pre-treatment in the IL-10 level(χ2=2.33, P>0.05). The IL-10 level after 6th week and after 22nd week were all lower than pre-treatment levels(χ2=4.08, 4.08, P<0.05, <0.05). There were no statistical difference between after and pre-treatment(χ2=0.084, 2.504,3.818,P>0.05,>0.05,>0.05)in IL-1β level.@*Conclusion@#After treatment with tocilizumab, the levels of serum IL-6 and IL-2R are helpful to assess the activity of SoJIA and the efficacy of therapy.

Efficacy and safety of tocilizumab on refractory systemic onset juvenile idiopathic arthritis:observation on 16 cases / 中国实用儿科杂志

OBJECTIVE: To observe the efficacy and safety of tocilizumab against refractory systemic onset juvenile idiopathic arthritis(SoJIA). METHODS: A prospective follow-up study of 16 patients with refractory active SoJIA patients with or with tocilizumab after treatment of clinical disease activity indicators and safety. The ANOVA was used for statistical analysis. RESULTS: After 2 weeks,12 weeks and 52 weeks of treatment,the levels of white blood cells,erythrocyte sedimentation rate and hypersensitive C-reactive protein were significantly decreased,and there were statistically significant differences(F=26.25、145.70、517.96,P<0.05). JADAS27 was significantly decreased after 2 weeks,12 weeks and 52 weeks of treatment with tocilizumab(the score being 23.09±3.46,8.19±2.63,4.25±2.86 and 2.63±1.54),the difference being statistically significant(P<0.05). Some children had adverse reactions,2 cases of skin abnormalities,1 case of white pityriasis,1 case of skin infection;3 cases of liver enzyme abnormalities;2 cases of leukopenia. CONCLUSION: Tocilizumab can improve the condition of children with SoJIA in rapid and obvious way,and medium and longterm security and tolerance was good. The duration of tocilizumab therapy should be carefully assessed.

Pay attention to the diagnosis and treatment of systemic-onset juvenile idiopathic arthritis / 中华实用儿科临床杂志

There is no specific clinical manifestation and laboratory test,the diagnosis of systemic-onset juvenile idiopathic arthritis (SoJIA) becomes difficuh.Some patients complicate with macrophage activation syndrome,if they are not treated timely,the mortality will be very high.Some patients were poor response to drug therapy,the disease relapsed frequently.So,they should pay attention to this difficult and serious disease in children.Diagnosis and treatment of SoJIA will be mainly elaborated below to enhance the level of diagnosis and treatment,and to improve the long-term prognosis of SoJIA.

Recognition of macrophage activation syndrome / 中华实用儿科临床杂志

Macrophage activation syndrome (MAS)is a serious potentially life -threatening complication seen primarily in patients with systemic onset juvenile idiopathic arthritis (sJIA).Clinical symptoms include persis-tent fever,liver and spleen lymph node enlargement,cytopenia,hyperferritinemia,hypofibrinogenemia,hypertriglyceri-demia,coagulation disorders,and hemophagocytosis can be seen in the bone marrow.This article summarizes the characteristics of MAS occurring in the context of sJIA and discuss the recent advances in classification systems and management.

Extremely elevated IL-18 levels may help distinguish systemic-onset juvenile idiopathic arthritis from other febrile diseases

The aim of this research was to explore whether IL-18 can be a serological marker for the diagnosis of systemic-onset juvenile idiopathic arthritis (sJIA). A total of 23 sJIA patients (13 males, median age 8.2), 20 acute lymphoblastic leukemia (ALL) patients, 18 patients with severe infections (SIF), 26 Kawasaki disease (KD) patients, 18 juvenile idiopathic arthritis (JIA) patients, and 25 healthy control patients were selected for this study. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum concentrations of the S100A8, S100A9, and IL-6 proteins. The serum IL-18 levels were detected by a cytometric bead array (CBA). The serum IL-6 concentrations in various disease groups were significantly higher than that in the healthy control group. The IL-6 concentrations exhibited no significant difference between disease groups. The S100A8 level in the sJIA group was significantly higher than those of the ALL, JIA, and healthy control groups but showed no significant difference compared to the SIF and KD groups. The S100A9 serum concentration in the sJIA group was significantly higher than those in the ALL and healthy control groups and exhibited no significant difference from the SIF, KD, and JIA groups. The IL-18 level of the sJIA group was significantly higher than that of the other febrile disease groups. The IL-18 serum concentration may be used as a biological serum marker to distinguish sJIA from other febrile diseases.

Severe hepatic injury for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis / 中华风湿病学杂志

Objective To analyze the clinical features and laboratory data of 10 patients with macrophage activation syndrome (MAS) complicating systemic onset juvenile idiopathic arthritis (soJIA),which were characterized by acute severe liver injury.Methods Data of 10 patients with soJIA/MAS from Nanjing Children's Hospital were collected retrospectively.The clinical features,laboratory findings,treatment,outcomes and prognosis were analyzed.Results In the total 10 patients,female (6/10) outnumbered male.Their age ranged from 1.5 to 9.5 years old (average 5.2±2.6).The most remarkable clinical manifestations were severe liver injury without systemic features,representing as hepatomegaly (10/10),splenomegaly (2/10) and strikingly increased transaminase (10/10,median:ALT 1 445 U/L,AST 885 U/L).Central nervous system dysfunction and hemorrhages were recorded in 20％ of the patients.Two patients had pulmonary infection.Laboratory data showed that platelet count was less than normal or precaution value (10/10,≤262×10g/L).Hyperferritinaemia (10/10,median:17 329 mg/ml) and soluble CD25 elevation (median:3 140 U/ml) were common in the soJIA/MAS patients.Evidence of macrophage hemophagocytosis was found in 90％ of the patients (9/10) who underwent bone marrow aspiration.Pathological findings of liver biopsy from 1 patient revealed massive infiltration of mononuclear cells in the portal tracts.Nearly all patients (9/10) received intravenous pulse methylprednisolone therapy,combined with cyclosporine A and high-dose intravenous immunoglobulin.Eight patients had good outcome.Only 2 patients were complicated with severe interstitial lung disease during 12-months follow-up.Conclusion MAS should be considered when patients with soJIA represents acute severeliver injury without systemic features combined with other laboratory data.Intravenous pulse methylprednisolone and cyclosporine A therapy may improve the prognosis of soJIA/MAS.

Research progress of Kawasaki disease and arthritis in children / 国际儿科学杂志

Kawasakd disease(KD) or incomplete KD(IKD) is a systemic vasculitis predominantly affecting young children.Clinical manifestations include fever with no obvious origin,skin damage,abnormalities of mucous membrane and lymph nodes.The disease is often accompanied by serious cardiovascular complications such as coronary artery aneurysm,therefore it attracts more and more attention.But arthritis or arthralgia complicates over one-third of KD or IKD patients.So early-onset arthritis is often indistinguishable from early juvenile idiopathic arthritis,especially systemic-onset juvenile idiopathic arthritis(SoJIA).KD and SoJIA are considered to be different diagnoses for children with long-term fever,rash,swollen lymph nodes,and more importantly,the treatment procedures are very different,but it is difficult to completely distinguish the two diseases,especially the IKD and early SoJIA.So in this paper,we will summarize the relationship between KD and arthritis in children,which aims to remind clinicians to pay attention for the diagnosis of KD and IKD.We suggest that physicians should be alert of the fact that they must individualize every patient's management,rather than merely care by the guidelines,which will delay the treatment.

Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica / Macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis

A síndrome de ativação macrofágica (SAM) é uma doença rara e potencialmente fatal, normalmente associada às doenças reumáticas crônicas, em especial a artrite idiopática juvenil. É incluída no grupo das formas secundárias de síndrome hemofagocítica, cujas outras causas podem ser as doenças linfoproliferativas e infecções. As manifestações clínicas e laboratoriais mais importantes são a febre não remitente, esplenomegalia, hemorragias, disfunção hepática, citopenias, hipoalbuminemia, hipertrigliceridemia e hiperferritinemia. O tratamento deve ser iniciado rapidamente, e a maioria dos casos responde bem aos corticosteroides e à ciclosporina (CSA). O vírus Epstein-Barr (EBV) é descrito como possível gatilho para muitos casos de SAM, especialmente naqueles em tratamento com bloqueadores do fator de necrose tumoral (TNF). Nos casos refratários ao tratamento convencional, etoposide (VP16) deve ser administrado, em associação com corticosteroides e CSA. Nosso objetivo foi descrever um caso raro de síndrome hematofagocítica provavelmente secundária à infecção pelo vírus Epstein-Barr (EBV), em paciente com artrite idiopática juvenil sistêmica, confirmada pelas manifestações clínicas e laboratoriais típicas, mielograma e sorologia positiva contra o EBV, que atingiu remissão completa após inclusão no protocolo de tratamento HLH-04.

Machrophage activation syndrome (MAS) is a rare and potentially fatal disease, commonly associated with chronic rheumatic diseases, mainly juvenile idiopathic arthritis. It is included in the group of secondary forms of haemophagocytic syndrome, and other causes are lymphoproliferative diseases and infections. Its most important clinical and laboratorial manifestations are non-remitting fever, splenomegaly, bleeding, impairment of liver function, cytopenias, hypoalbuminemia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia. The treatment needs to be started quickly, and the majority of cases have a good response with corticosteroids and cyclosporine. The Epstein–Barr virus is described as a possible trigger for many cases of MAS, especially in these patients in treatment with tumor necrosis factor (TNF) blockers. In these refractory cases, etoposide (VP16) should be administered, associated with corticosteroids and cyclosporine. Our objective is to describe a rare case of MAS probably due to EBV infection in a subject with systemiconset juvenile idiopathic arthritis, which achieved complete remission of the disease after therapy guided by 2004-HLH protocol.

T helper lymphocyte subsets and cytokines in children with systemic-onset juvenile idiopathic arthritis / 临床儿科杂志

Objectives To explore the changes of T helper (Th) lymphocyte and its related factors in children with syste-mic-onset juvenile idiopathic arthritis (SoJIA). Methods A total of 36 SoJIA inpatients, hospitalized from January 2012 to June 2013, were divided into active phase group and remission group. In addition, 20 healthy children were selected as normal con-trols. Th1, Th2 and Th17 cell ratios in peripheral blood mononuclear cells were detected and compared between each group by flow cytometry. Serum interferon-γ(INF-γ), interleukin-4 (IL-4), interleukin-17 (IL-17) levels were measured by enzyme-linked immunosorbent assay. Results The proportions of Th17 cells over CD3+CD8-cell were (3.30±2.15)%, (1.78±1.14)%and (1.22± 1.14)%in active phase group, remission group and control group. The difference among three groups was significant (H=14.437, P=0.001), and the active phase group had higher proportion of Th17 than the other two groups (P0.05). The serum IL-17 levels were (125.82 ± 45.87) pg/ml, (57.79±25.84)pg/ml and(50.02±18.37)pg/ml in active phase group, remission group and control group with signifi-cant difference among three groups (F=31.82, P=0.000), and the active phase group had higher level of IL-17 than the other two groups (P0.05). Conclusions Acquired cellular immunity is involved in pathogenesis of SoJIA, the increased proportion of Th1 and Th17 cell and the changes of related cytokines seem to correlate with active phage of SoJIA.

Leflunomide in Systemic Onset Juvenile Idiopathic Arthritis.

Methotrexate, the mainstay of treatment in Juvenile idiopathic arthritis, might not be effective in a few patients of polyarticular and systemic onset juvenile idiopathic arthritis. Use of biologicals like TNF-α blockers, the next line of preferred drugs is constrained by the high cost. We successfully used leflunomide in four patients.

Renal cell carcinoma and systemic onset juvenile idiopathic arthritis.

Renal cell carcinoma (RCC) accounts for majority of malignancies arising out of the kidney. Paraneoplastic rheumatologic manifestations; myositis, vasculitis, and arthritis have been described in a few cases with RCC. Systemic onset juvenile idiopathic arthritis (JIA) is characterized by intermittent fever, arthritis, reticulo-endothelial cell hyperplasia and absence of rheumatoid factor and antinuclear antibodies. Herein, we report a 16-year-old boy with systemic onset JIA for 5 years who developed RCC and his systemic and articular symptoms paralleled the course of RCC. The common pathophysiologic influence of the cytokine Interleukin-6 possibly played a role in the exacerbation of symptoms of systemic onset JIA during the relapse of the RCC. The case is presented to highlight the rare co-occurrence of these two diseases and their influence on each other.