Anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

Anticyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile idiopathic arthritis (JRA), particularly in those with polyarticular JIA. We analyzed the presence of anti-CCP antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups. One hundred and fifty-nine serum samples were investigated. Forty-five patients were diagnosed with JIA (15 male and 30 female) aged 1.9–17.3 years (median 12.9, mean 11.0). Thirty-eight samples were taken from patients suffering from other autoimmunopathies and 34 patients with other underlying diseases were taken at different time points in their disease course. Under 42 samples were taken from patients with noninflammatory diseases. Enzyme-linked immunosorbent assay (ELISA) was used for the detection of anti-CCP antibodies. Anti-CCP antibodies were found in 6.9% of all samples and in 4.4% patients with JIA. Disease duration and medication did not differ significantly between anti-CCP positive and negative patients. A review of the literature and our own results shows that anti-CCP antibodies can be detected in the sera of only some patients with JIA. Routine determination of anti-CCP cannot be recommended.     

Anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

Abstract

Anticyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile idiopathic arthritis (JRA), particularly in those with polyarticular JIA. We analyzed the presence of anti-CCP antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups. One hundred and fifty-nine serum samples were investigated. Forty-five patients were diagnosed with JIA (15 male and 30 female) aged 1.9–17.3 years (median 12.9, mean 11.0). Thirty-eight samples were taken from patients suffering from other autoimmunopathies and 34 patients with other underlying diseases were taken at different time points in their disease course. Under 42 samples were taken from patients with noninflammatory diseases. Enzyme-linked immunosorbent assay (ELISA) was used for the detection of anti-CCP antibodies. Anti-CCP antibodies were found in 6.9% of all samples and in 4.4% patients with JIA. Disease duration and medication did not differ significantly between anti-CCP positive and negative patients. A review of the literature and our own results shows that anti-CCP antibodies can be detected in the sera of only some patients with JIA. Routine determination of anti-CCP cannot be recommended.     

Significance of calgranulins (S100A8, S100A9 and S100A12), ferritin and toll-like receptor 4 in juvenile idiopathic arthritis children

Aim of the workTo evaluate role of calgranulins (S100A8, S100A9, and S100A12), ferritin and toll-like receptor 4 (TLR4) in juvenile idiopathic arthritis (JIA) children.Patients and methodsSera of 59 JIA Iraqi patients and 58 healthy-matched children were studied and serum levels of S100A8, S100A9, S100A12, ferritin and TLR4 assessed. Juvenile arthritis disease activity score-27 (JADAS27) was assessed.ResultsThe mean age of the patients was 10.1 ± 4.2 year; they were 40 females and 19 males with disease duration of 2.4 ± 2.6 years. The levels of S100A9 and ferritin were significantly increased in JIA patients compared to control (98 ± 63 vs. 65 ± 53 ng/ml; p = 0.004 and 57 ± 52 vs. 33 ± 31 ng/ml; p = 0.003, respectively), while S100A8, S100A12 and TLR4 levels showed no significant differences. Significant correlations were found; S100A8 with S100A9 (r = 0.27; p = 0.036) and TLR4 (r = 0.73; p = 0.001), S100A9 with TLR4 (r = 0.29; p = 0.026), and S100A12 with ferritin (r = 0.58; p = 0.001). S100A8, S100A9 and ferritin could significantly discriminate JIA from control (p = 0.035, p = 0.001, and p = 0.001, respectively). Corresponding sensitivities of S100A8, S100A9 and ferritin were 63%, 70% and 61%, and specificities were 60%, 66% and 60% at cutoff values of 28.3, 68.4 and 29.6 ng/ml, respectively. On multinomial logistic regression analysis, S100A9 and ferritin were significant predictors especially in those with positive C-reactive protein (CRP) and rheumatoid factor (RF), low JADAS27 and persistent oligoarthritis subtype.ConclusionsS100A8, S100A9 and ferritin were upregulated in sera of JIA patients. Their significance as predicting biomarkers of disease outcome was augmented, especially in CRP- and RF-seropositive, low JADAS27 and persistent oligoarticular JIA patients.     

Chitotriosidase activity in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is an inflammatory joint disease of unknown etiology. The pathogenesis is driven by T and B cells. The role of macrophages remains unclear. Chitotriosidase belongs to the chitinase protein family and is secreted by activated macrophages. The chitinases are able to catalyze the hydrolysis of chitin or chitin-like substrates such as 4-methylumbelliferyl chitotrioside. Chitotriosidase activity was determined using the substrate 4-methylumbelliferyl beta-DNN'N'-triacetylchitotrioside (4-MU-TCT, SIGMA Chemical Co.). The substrate and serum were incubated with the serum in a citrate/phosphate buffer. The reaction was stopped by adding a buffer (Na(2)CO(3)). The fluorescence of 4-methylumbelliferone was evaluated by fluorimeter at excitation 360 nm and emission 450 nm. We report about chitotriosidase measurements in patients with JIA. The chitotriosidase level in synovial fluid was up to approximately 1,000 nmol/(h ml) at disease onset before therapy. The level in the sera was below 600 nmol/(h ml). Serum chitotriosidase levels could represent the activity of macrophages in the synovial fluid in JIA.     

Serum,synovial and mRNA expression of interleukin-33 in juvenile idiopathic arthritis patients: Potential role as a marker of disease activity and relation to musculoskeletal ultrasound

Aim of the workTo measure interleukin-33 (IL-33) serum and synovial fluid (SF) levels as well as its relative expression in peripheral blood mononuclear cells (PBMC) of juvenile idiopathic arthritis (JIA) patients and to study their relation to clinical, laboratory and musculoskeletal ultrasound characteristics, disease activity and functional status.Patients and methodsThe study included 60 JIA patients and 60 healthy controls and SF levels were measured in 20. Juvenile arthritis disease activity score (JADAS27) and Juvenile Arthritis Multidimensional Assessment Report (JAMAR) were assessed; Ten-joint grey scale (GS) and power Doppler (PD) MSUS score was performed. Rheumatoid factor (RF) titer and C-reactive protein (CRP) levels were measured.ResultsIn JIA patients, serum IL-33 levels (median 12.6; 7.4–23.8 ng/l) and its relative mRNA expression (median 3.3; 2.5–3.7) were significantly higher than their levels in the controls (median 1.7; 0.8–2.4 ng/l and median 1 ng/ml; p < 0.001). Polyarticular subtype (n = 20) had higher IL-33 serum levels compared to oligoarticular (n = 28, p < 0.001) and systemic-onset (n = 12, p = 0.006) subtypes. In JIA patients, the serum and SF levels of IL-33 significantly correlated with JADAS27 (p < 0.001 and 0.002 respectively), CRP (p < 0.001 and 0.007 respectively), GS (p < 0.001 and 0.001 respectively) and PD (p < 0.001 and 0.005 respectively). Serum IL-33 correlated with RF (p = 0.039) while, SF IL-33 correlated with physical function (p = 0.02).ConclusionsJIA patients have significantly elevated IL-33 serum concentrations and mRNA expression that considerably correlated with different inflammatory parameters, RF and physical function suggesting that it could be a valuable marker of JIA disease activity and implies a possible prognostic role.     

Vascular cell adhesion molecule-1 (VCAM-1), flow mediated dilatation (FMD) and carotid intima media thickness (IMT) in children with juvenile idiopathic arthritis: Relation to disease activity,functional status and fatigue

Background

There is risk of premature atherosclerosis in juvenile idiopathic arthritis (JIA) patients which predisposes to cardiovascular disease (CVD) in adulthood. This can be assessed by flow mediated dilatation (FMD) and carotid intima media thickness (IMT) of the arterial wall and by soluble vascular cell adhesion molecule (sVCAM-1).

Analysis of childhood reactive arthritis and comparison with juvenile idiopathic arthritis

There is currently no agreement on how to classify and diagnose reactive arthritis (ReA) and what kind of clinical and laboratory findings are specific for the diagnosis. This study retrospectively analyzed the initial clinical manifestations and laboratory findings in children diagnosed with ReA and juvenile idiopathic arthritis (JIA). A comparison was also made between these two groups to see if there were differences. A retrospective chart review was performed and 44 patients diagnosed with ReA and 80 patients with JIA were enrolled in this study. Their initial clinical manifestations and laboratory findings were also analyzed and compared. The initial clinical manifestations in ReA were analyzed including the demographic data, the preceding infection history, the duration of the infectious episode to the onset of arthritis, the duration of arthritic symptoms, and the involved joint pattern. Comparison of the initial laboratory findings between patients with ReA and JIA showed significant differences between erythrocyte sedimentation rates (ESR) in the first hour, platelet counts (p<0.05), and ESR in the second hour (p=0.052). Further, comparing ReA with the subtypes of JIA, significant differences were noted between ReA and the systemic type in terms of hemoglobin level, platelet counts, C-reactive protein, and first and second hour ESR (p<0.05). However, if compared with the polyarticular or pauciarticular type, only the platelet counts showed any significant statistical difference (p<0.05). This study summarizes clinical experiences in ReA. The differences in laboratory findings of ReA and JIA may provide a clue in making a differential diagnosis.     

Hip involvement in juvenile idiopathic arthritis

We analyzed the clinical, biological, and radiological aspects of hip involvement in juvenile idiopathic arthritis (JIA) in a developing country. The recruited patients fulfilled the International League Against Rheumatism criteria for the diagnosis of the JIA. Clinical, biological, and radiological parameters relating to the JIA were collected. Hip involvement was assessed according to clinical and radiological data related to hip disease. One hundred twenty-one patients were included (68 girls and 53 boys). The mean age of the disease onset was 9 ± 4.2 years (1–16 years).The mean age of the patients at the time of the study was 15 ± 10 years (2–46 years). The duration of the disease was 5 ± 8.5 years (0.5–39 years). Forty cases (33%) of the hip involvement were noted. The mean age was 24 ± 10.03 years (3–46 years); the sex ratio was 1:3. The mean duration of the hip disease was 0.6 ± 3.6 years (3–14 years). Hip arthritis seemed to be more frequent in polyarticular and enthesitis-related arthritis. The severity of the hip involvement was significantly correlated with early disease onset, disease duration, subtypes, and high disability (for all these data p < 0.05). This study suggested that in JIA hip involvement was more frequent in enthesitis-related arthritis and polyarticular subtypes. It was correlated with the severity and the early disease onset of the JIA, which was similar to reported data.     

Differential plasma microRNAs expression in juvenile idiopathic arthritis

Objectives. To identify potential novel biomarkers for juvenile idiopathic arthritis (JIA), we evaluated the correlation between plasma expression levels of specific miRNAs and disease characteristics of JIA.

Methods. Differentially expressed miRNAs in JIA plasma were identified by microarray analysis. Five candidate plasma miRNAs with differential expression were further evaluated by qRT-PCR. The correlation between the expression of candidate plasma miRNAs and clinical parameters of JIA patients was assessed.

Results. The expression of miR-16, miR-146a, and miR-223 was higher, and miR-132 was lower, in the plasma of JIA patients as compared with healthy subjects and juvenile ankylosing spondylitis patients (p < 0.05). Plasma miR-16 concentrations were considerably higher for polyarticular JIA patients than oligoarticular JIA patients and correlated with the juvenile arthritis magnetic resonance imaging scores for the hip and plasma interleukin-6 or IL-6 levels. Additionally, miR-146a levels correlated directly with the Juvenile Arthritis Disease Activity Scores in 27 joints, the swollen joint count, the limited joint count, and the juvenile arthritis magnetic resonance imaging scores for the hip, but correlated inversely with plasma tumor necrosis factor-α or TNF-α levels.

Conclusions. This study demonstrates that the expression of plasma miRNAs correlates with JIA disease and suggests that plasma miR-16 and miR-146a have potential novel value for JIA diagnosis.     

Guidance on using tocilizumab for juvenile idiopathic arthritis

Abstract

Medical care for rheumatic disease in children has been supported by advances in rheumatology. In the past few years and based on knowledge about cytokines, particularly marked advances have been made in treatments using biological products. The fact that patients showed a marked response to treatment with biological products also provided uniform direction to treatment choice, which had previously been chaotic. On the other hand, biological products inhibit the action of physiologically essential substances, such as inflammatory cytokines or their receptors. This led to concerns about the risk of fatal or life-threatening adverse reactions, and rheumatologists are now required to take a disciplined approach to the use of these products. Thus, we sincerely hope that this guidance on using tocilizumab for juvenile idiopathic arthritis serves as a desk reference for pediatric rheumatologists and other healthcare professionals treating children with rheumatic diseases by biological drugs.     

Open reduction of the dislocated hip in juvenile idiopathic arthritis: a case report

Abstract

An 8-year-old girl with systemic-onset juvenile idiopathic arthritis (JIA) required surgical reduction for a dislocated left hip joint following failure of skin traction for 1 week. Unaided walking was achieved by 3 months postoperatively. Incongruence and irregularity of the hip joint remained but may resolve with maturation. Joint laxity caused by synovitis, flexion/adduction contracture with pain, and acetabular dysplasia by growth disturbance apparently caused hip dislocation.     

Open reduction of the dislocated hip in juvenile idiopathic arthritis: a case report

An 8-year-old girl with systemic-onset juvenile idiopathic arthritis (JIA) required surgical reduction for a dislocated left hip joint following failure of skin traction for 1 week. Unaided walking was achieved by 3 months postoperatively. Incongruence and irregularity of the hip joint remained but may resolve with maturation. Joint laxity caused by synovitis, flexion/adduction contracture with pain, and acetabular dysplasia by growth disturbance apparently caused hip dislocation.     

Characteristics of FDG-PET findings in the diagnosis of systemic juvenile idiopathic arthritis

Objective: To examine and delineate inflammatory focus in patients with juvenile idiopathic arthritis (JIA), ¹⁸F-Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) (¹⁸F-FDG-PET) was applied to patients with JIA, and the images of these patients were compared.

Methods: Sixty-eight children (59 with systemic JIA (s-JIA) and 9 with polyarticular JIA) were included. The diagnosis of JIA was done to meet the International League of Associations for Rheumatology (ILAR) criteria. After 6-h fasting, whole-body positron emission tomography (PET) scans were acquired 60 min after intravenous injection of 3–5 MBq/kg ¹⁸F-FDG. The interpretation of ¹⁸F-FDG uptake was based on visual characteristics.

Results: Two types of PET images were outstanding in s-JIA; one was ¹⁸F-FDG uptake in red bone marrow, such as the spine, pelvis, and long bones as well as spleen (12 cases), and other type was the uptake in the major joints, such as hips, elbows, wrists, knees, and ankles (8 cases). The former findings were correlated with elevated levels of inflammatory markers, while the latter were with significantly increased levels of MMP-3 (p?<?0.05).

Conclusion: There was a noticeable accumulation of ¹⁸F-FDG uptake in bone marrow of s-JIA patients which may indicate the inflammatory focus of this disease and play an important role in the pathogenic basis of arthritis and systemic inflammation of s-JIA.     

Articular damage in adults with juvenile idiopathic arthritis

The goal of this study was to assess the long-term articular damage in adults with juvenile idiopathic arthritis (JIA) using the Rheumatoid Arthritis Articular Damage (RAAD) score and to determine any associations between the disease-related parameters and RAAD score. Thirty-eight adults identified with JIA at 18 years of age or older with disease duration of at least 5 years were assessed by means of the RAAD score. Patients were divided into three groups according to disease duration as 5-10 years (group 1), 11-15 years (group 2) and more than 16 years (group 3), and into three groups according to JIA subtypes as seropositive polyarticular (group A), seronegative polyarticular (group B), and oligoarticular (group C). Functional disability, functional status, disease activity and depression were measured by Health Assessment Questionnaire (HAQ), Steinbrocker classification, Disease Activity Score 28 (DAS 28), and Beck Depression Inventory, respectively. We investigated any possible associations between the RAAD score and groups, sex, age at onset of the disease, HAQ, Steinbrocker classification, DAS 28, and Beck Depression Inventory. We observed significant differences in RAAD scores according to groups A, B, C (p < 0.01), but not according to groups 1, 2, 3 or sex (p > 0.05). While the RAAD score correlated well with HAQ (p < 0.001), Steinbrocker classification (p < 0.001) and DAS 28 (p < 0.01), it did not correlate with age at onset of the disease (p > 0.05) or Beck Depression Inventory (p > 0.05). Seropositive polyarticular patients demonstrate the worst articular damage scores. Even though articular damage does not progress over time and JIA frequently has a benign course, care should be given to establishing regular follow-up periods and well-arranged treatments, especially for seropositive polyarticular groups, to maintain satisfactory long-term disease outcome throughout the lives of JIA patients.     

Guidance on the use of adalimumab for juvenile idiopathic arthritis in Japan

Abstract

Adalimumab is a monoclonal antibody produced by DNA recombination technology, and is the first human monoclonal antibody against human tumor necrosis factor (TNF)-α in the world. Adalimumab binds with high affinity and specificity to soluble TNF-α and normalizes its biological action. The clinical development of adalimumab started in Europe. Adalimumab was approved for the treatment of rheumatoid arthritis (RA) in December 2002 in the United States and in September 2003 in the European Union. Since then, adalimumab has been approved for the expanded indications of psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), psoriasis (Ps), and juvenile idiopathic arthritis (JIA) in the United States and the European Union, and it is now used widely for the treatment of these diseases. In Japan, adalimumab was approved for the treatment of RA in April 2008, and its use was approved for the indications of Ps and PsA in January 2010, and for CD and AS in October 2010. In Japan, children who have been diagnosed and treated according to the “Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)” (published in this journal in 2007; see reference 1 in the main text), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adherence to the indications and exclusion criteria and should be used, for the time being, only by physicians trained in how to use them. In Japan, adalimumab was approved for the treatment of JIA in July 2011. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidance presented here define the indications, exclusion criteria, usage, and evaluation criteria of adalimumab for the treatment of polyarticular JIA.     

Therapeutic advancements in juvenile idiopathic arthritis

The treatment of juvenile idiopathic arthritis (JIA) has substantially evolved over the past two decades. Research has been conducted and is ongoing on how therapies can best be utilized either as monotherapy or in combination for enhanced efficacy. The introduction of biologic therapies that selectively target specific cytokines has changed the acceptable clinical course of childhood arthritis. In addition to the development and utilization of new therapeutic agents, the pediatric rheumatology community has made vital progress toward defining disease activity, developing validated outcome measures, and establishing collaborative networks to assess both clinical outcomes and the long-term side effects related to therapeutics for juvenile arthritis. In this chapter, we will discuss the therapeutic evolution in JIA over the past two decades. Although the largest strides have been made with biologic agents, and these newer drugs have more rigorous data to support their use, select commonly used non-biologic therapies are included, with the discussion focused on more recent updated literature.     

Serological screening for coeliac disease in patients with juvenile idiopathic arthritis

Background and study aimsJuvenile idiopathic arthritis (JIA) is characterized by autoimmune aetiology. A gene locus 4q27 related to rheumatoid arthritis, psoriatic arthritis, and coeliac disease is associated with susceptibility to JIA. There are reports indicating several patients with JIA had been diagnosed with CD. We aimed to assess the frequency of coeliac disease (CD) in patients with juvenile idiopathic arthritis (JIA).Patients and methodsThis prospective study was carried out from October 2015 to August 2016 and included 96 patients with JIA. All patients were evaluated in terms of clinical and laboratory findings of CD. Levels of total IgA and tissue transglutaminase antibody (tTG) IgA were measured in all patients. Those with increased level of tTG IgA were further tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy were planned for a definite diagnosis of CD in patients with positive EMA.ResultsOf the 96 patients in our study, 34 (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had ERA form, 11 (11.5%) had systemic form, and 10 (10.4%) had psoriatic form. Sixteen of our patients (16.6%) were not using any drugs during the study. Neither EMA IgA antibodies were analysed nor gastro-duodenoscopy was performed because no patients were positive for tTG IgA. There was no difference in terms of tTG levels between the patients using NSAIDs or other drugs.ConclusionWe did not find CD in children with JIA. Long term studies with more JIA patients are needed to provide more precise interpretation.     

Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis

The objective of this report is to explore the balance between serum and synovial fluid levels of interleukin (IL)-18 in children with juvenile idiopathic arthritis (JIA). Blood samples were obtained from 81 children with JIA and 18 control children. Synovial fluid samples were collected from 16 children with oligoarticular JIA. Concentrations of IL-18 were determined using commercial kit. Patients with systemic JIA had higher serum levels of IL-18 than patients with other forms of JIA or control children, both during the active (median, range: 6,240, 1,600–78,750 pg/ml) and inactive (1,615, 513–3,270 pg/ml) phase of disease [analysis of variance (ANOVA), P < 0.05). Levels of IL-18 in sera of children with oligoarticular JIA (255, 89–4,342 pg/ml) were similar to the respective synovial fluid levels (217, 89–1,245 pg/ml). Serum levels of IL-18 were proportional to the erythrocyte sedimentation rate and levels of C-reactive protein, but inversely proportional to the haemoglobin levels. IL-18 appears to be an important mediator of systemic JIA, while it seems of a lesser relevance in pathogenesis of other JIA forms. Therefore, inhibition of IL-18 might be a base for a successful biological therapy for systemic JIA.     

Antinuclear antibody-positive cohort constitutes homogeneous entity in juvenile idiopathic arthritis

Objective. To identify a homogeneous entity for antinuclear antibody (ANA)-positive patients suffering from juvenile idiopathic arthritis (JIA).

Methods. All of the clinical features were recorded retrospectively. ANA positivity was defined as more than twice positive results at a titer of > 1:100. The correlation between ANA positivity and clinical parameters was assessed by multiple logistic regression analysis.

Result. Of 120 patients, 49 patients were ANA positive (31 oligoarthritis, 18 rheumatoid factor [RF]-negative polyarthritis) and 71 patients were ANA negative (48 oligoarthritis, 23 RF-negative polyarthritis), and were recruited retrospectively to this study according to the International League of Associations for Rheumatology (ILAR) criteria. In ANA-positive cohort, the characteristics of early-onset age, female predominance, and asymmetric arthritis were observed compared with ANA-negative cohort including oligoarthritis and RF-negative polyarthritis. Correspondingly, we found that ANA-positive cohort had higher cumulative number of joints affected at 9 and 12 months after disease presentation than ANA-negative cohort, had lower frequency of occurrence of image change, and had a different pattern of affected arthritis than ANA-negative cohort, which was more likely to have knee involvement and less likely to have hip and shoulder involvement. ANA positivity correlated strongly with asymmetric arthritis, female predominance and wrist involvement.

Conclusion. This study demonstrates that ANA-positive cohort divided into different subgroups by present ILAR criteria share the similar features and suggests that ANA positivity might serve as a novel potential value for JIA classification.     

Nitric oxide levels and the severity of juvenile idiopathic arthritis

In this study, we evaluate the distribution of nitric oxide (NO) in the serum of juvenile idiopathic arthritis (JIA) patients, correlating it with parameters of the severity of the disease. Ninety-seven patients with mean age 11.7 years and disease duration 4.8 years, showing active disease or not, grouped as oligoarticular (n = 34), polyarticular (n = 29) and systemic (n = 34) group, presenting uveitis and positive RF with erosive arthritis or active disease and erosions had significantly high levels of NO than the inactive ones. NO correlated with TNF-α in the oligoarticular subtype (P < 0.03), with pain in the polyarticular subtype with active disease (P < 0.04) and with ESR in the systemic subtype with active disease (P < 0.03). TNF-α concentration was high in all patients with active disease, accompanying NO production. The data confirm the production of NO in JIA patients, indicating a possible positive correlation between the production of NO and severity of the disease.