Treatment of patients with juvenile idiopathic arthritis (JIA) in a population-based cohort

A population-based cohort was utilized to evaluate medications and intra-articular injection utilization for patients with juvenile idiopathic arthritis (JIA) to inform clinical practice and further research. In a geographically defined population, all incident cases of JIA cases were identified between January 1, 1994 and December 31, 2013 based first on diagnosis code followed by medical chart confirmation. Medications and intra-articular glucocorticoid injections were abstracted. Predictors of the first disease-modifying antirheumatic drug (DMARD)/biologic and injections were reported as a hazard ratio (HR) with 95 % confidence intervals (CIs) adjusted for age and sex. Kaplan-Meier methods evaluated therapy at 6 months and 1 year. Injections were reported per 100 person-years (py) with 95 % CI using the Poisson methods. Seventy-one incident cases were identified. Forty-two (59 %) were female with mean age (standard deviation) at diagnosis of 8.2 (5.3) years. Twenty-six (37 %) utilized at least one DMARD or biologic, in which 77 % of these were prescribed in the first 6 months. Subtype of JIA was significantly associated with DMARDs/biologics (p?<?0.001). Intra-articular injections were performed in 48 %. The rate of intra-articular injections was 20.7 per 100 py (95 % CI 16.5, 25.6). The rate of joint injections was higher in the first year after diagnosis (p?<?0.001) and more common in recent years (p?<?0.001). The majority of patients with JIA in a modern population-based cohort do not require DMARDs or biologics. In those who do, the majority receives these within the first 6 months. Intra-articular injections were utilized in almost half of patients with JIA and were increasingly used.     

Anti-BiP antibody levels in juvenile idiopathic arthritis (JIA)

SIR, We have previously described the human heat shock proteinBiP (immunoglobulin binding protein; glucose regulated protein78) as an autoantigen in rheumatoid arthritis [1]. Antibodiesto BiP have been described in the serum of RA patients by ourselvesand other groups [2, 3] and we have recently described anti-BiPantibodies in the synovial fluid of RA patients and the serumof patients with primary Sjögren's syndrome [3]. Moreoveranti-BiP antibodies have been shown to be elevated in animalmodels of arthritis [1]. The functions     

Premature ovarian failure in women with juvenile idiopathic arthritis (JIA)

OBJECTIVE: To examine the effect of longstanding juvenile idiopathic arthritis (JIA) on menstrual irregularity and the incidence of premature ovarian failure in women. METHODS: Women with longstanding JIA who had abnormal or absent menstrual cycles had their circulating levels of gonadotrophins measured to check for the presence of ovarian failure. Disease demographics and subsets, function, age at onset of menstrual irregularity, previous medical intervention, concurrent diseases and history of pregnancy/delivery were documented. RESULTS: 177/187 (95%) of female adults with JIA who were identified and contacted, participated in the study. The average age at review was 35.4 years (19-78) with average disease duration of 28.7 years. 47.4% of all patients had clinically active arthritis. 44.6% of all patients had severe disability (HAQ score > 1.5). Six patients had premature ovarian failure unrelated to medication use, comprising 3.4% of the females in the study, compared to an expected incidence of 1% in the general population (p < 0.01). In addition, three (1.7%) of these had onset of symptoms before age 30, compared to an expected incidence of 0.1% in the general population (p < 0.01). The average maternal age at first delivery in women with JIA (27.2 years) was higher than the general population (23.5 years). CONCLUSION: Idiopathic premature ovarian failure was more commonly found in individuals with juvenile idiopathic arthritis. In addition a small number of patients had iatrogenic premature ovarian failure related to chlorambucil use.     

Folate usage in MTX-treated juvenile idiopathic arthritis (JIA) patients is inconsistent and highly variable

Folate supplementation is widely accepted and utilized for the prevention of adverse events in juvenile idiopathic arthritis (JIA) patients who are treated with methotrexate. Despite the widespread use of folate supplementation, there is a lack of convincing evidence to support the role of folate in the enhancement of methotrexate efficacy and the prevention of methotrexate-related adverse events. In order to understand current practices used by experts, we surveyed 214 pediatric rheumatologists around the globe. Seventy-one unique folate supplementation regimens were reported for this study. Results indicated that folate supplementation (either in the form of folic acid or folinic acid) is inconsistent and highly variable within the United States as well as between the United States and other countries. This level of variability is often associated with lack of evidence and emphasizes the need for well-designed clinical trials to support a rational folate supplementation regimen in patients with JIA who are treated with methotrexate.     

Apoptosis of peripheral blood lymphocytes in patients with juvenile idiopathic arthritis

BACKGROUND: Recent data suggested that abnormalities in mechanisms regulating apoptosis may have a role in the development of the rheumatoid process. OBJECTIVE: To evaluate different aspects of apoptosis in children with juvenile idiopathic arthritis (JIA). METHODS: The frequency of TUNEL positive peripheral blood (PB) lymphocytes (apoptotic index (AI)), as well as serum CD95 (APO1/Fas) antigen expression and serum levels of sFas and interleukin 15 (IL15), were examined in 44 cases of JIA. Results were correlated with type of onset, activity of JIA, and acute phase indicators. RESULTS: The AI of lymphocytes was significantly higher in patients with JIA than in controls (p=0.020). The mean AI of lymphocytes was increased in JIA with systemic type of onset and high activity (p=0.001). Moreover, IL15 levels in systemic disease were higher than in controls (p=0.012). An increased AI correlated with raised IL15 (p=0.046), erythrocyte sedimentation rate (p=0.005) and C reactive protein (CRP; p=0.017). Additionally, correlation was found between IL15 and CRP levels (p=0.039). CD95 and sFas levels were unchanged compared with controls. CONCLUSION: PB lymphocytes of children with JIA have an increased tendency to undergo apoptosis. The degree of apoptosis depends on the type of onset and activity of JIA and correlates with serum levels of IL15. Further studies are needed to explain whether this is an epiphenomenon of the disease activity or is related to the pathogenesis of JIA.     

Anti-inflammatory effect by exclusive enteral nutrition (EEN) in a patient with juvenile idiopathic arthritis (JIA): brief report

There is extensive evidence for influence of gut microbiota on health. Exclusive enteral nutrition (EEN) possibly changes gut microbiota, but the exact pathophysiological role is unknown. EEN has been shown to have an anti-inflammatory effect in children with Mb Crohn, an inflammatory bowel disease. The intestinal tract is very scarcely studied in children with juvenile idiopathic arthritis (JIA), but data points to an immunologically important role. The aim of this study was to explore if EEN had any anti-inflammatory effect in children with JIA. The first patient enrolled in the study was followed for 1 year. She had onset of severe polyarticular disease at 3.2 years of age, negative in RF, anti-CCP, ANA, and HLA-B27. She was included in the study at 7.4 years of age. Exclusive enteral nutrition was given in two periods of almost 7 weeks each, several months apart, during the year of the study. Clinical and laboratory status were assessed before, during, and after treatment periods. In this patient, EEN had remarkable anti-inflammatory effect that was sustained for months after each of two separate treatment periods. Exclusive enteral nutrition is a possible anti-inflammatory treatment in patients with JIA, but to what extent EEN is effective in other children with JIA needs to be explored, as well as the possible pathophysiological role of EEN in those children.     

Design and validation of a new scale to assess the functional ability in children with juvenile idiopathic arthritis (JIA)

OBJECTIVE: The assessment of the functional ability is one of the items of the core set to define improvements in patients with JIA, CHAQ being the most used scale already validated in 32 countries. The aim of this study was to design and validate a new scale named CAPFUN (capacidad funcional = functional ability) to assess functional ability in children with JIA. METHODS: This scale includes 20 items, 8 of upper limbs, 8 of lower limbs, 3 combined, and 1 of cervical spine, developed in two steps according with OMERACT. Each item is scored: 0 when it is impossible to be performed, 1 when it is performed incompletely or with difficulties, and 2 when it is well performed. Seventy three patients with JIA according to ILAR criteria were assessed: 25 boys (34.2%) and 48 girls (65.8%) whose aver-age age was 12.8 years (95% CI 11.8 - 13.8) and the time from disease onset was 5.02 years (95% CI 3.9 - 6.1). For validation purposes, it was applied to 91 healthy children and adolescents. In every patient, correlation with active joints count and functional class according to Steinbrocker was assessed and with CHAQ in 31 patients in this series. RESULTS: The CAPFUN index obtained in all healthy children was 2. Patients' media CAPFUN index was 1.54 (95%CI 1.38 - 1.68). The CAPFUN index for Steinbrocker's class I was 1.84 +/- 1.8; for class II 1.60 +/- 1.5 and for class III 0.91 +/- 1 (F 24.1 p < 0.001). CAPFUN showed significant correlation with CHAQ (Spearman coefficient -0.79 p < 0.001), with active joints count (Spearman coefficient -0.72 p < 0.001) and with Steinbrocker functional classes (Spearman coefficient -0.69 p < 0.001). This scale showed a good internal reliability (alpha coefficient equal to 0.94), its construct validity is demonstrated by its good correlation with Steinbrocker's scale and with CHAQ. CONCLUSION: CAPFUN is a new instrument in order to assess functional ability in children with JIA. This scale showed a good internal reliability. Construct validity is demonstrated by its high correlation with Steinbrocker's scale and with CHAQ. This study demonstrates the usefulness of CAPFUN for the assessment of functional ability in children with JIA.     

Ex vivo apoptosis,CD95 and CD28 expression in T cells of children with juvenile idiopathic arthritis

We hypothesise that T-cell apoptosis and the percentage of T cells expressing molecules involved in apoptosis modulation (CD95, CD28) are altered at the inflammation site and in peripheral blood (PB) of children with juvenile idiopathic arthritis (JIA). Paired JIA samples of synovial fluid (SF) and PB ( n=7) and PB samples from age-matched normal children ( n=23) were analysed immediately ex vivo. Apoptosis was measured by detection of phophatidylserine (PS) externalisation on T cells. CD95 or CD28 was detected by FACS, and soluble CD95 and CD95 ligand levels were detected by enzyme-linked immunosorbent assay (ELISA). In SF, the mean percentage of apoptotic T cells was somewhat higher than in PB. However, the percentages of T cells expressing CD95 and soluble CD95 levels were markedly higher in SF (CD4 cells 96+/-2%, CD8 91+/-6%, soluble CD95 6,420+/-2,571 pg/ml) than in PB (CD4 32+/-10%, CD8 36+/-9%, soluble CD95 4,296+/-2,142 pg/ml). Peripheral blood T-cell apoptosis in JIA (CD4 20+/-8%, CD8 42+/-19%) was higher than in the control group (CD4 5+/-2%, CD8 9+/-6%). Interestingly, the percentage of PB CD4 cells expressing CD28 was lower in JIA than controls. In conclusion, systemic T-cell apoptosis was higher in JIA while a substantial number of SF T cells survived locally, despite the fact that almost all cells express CD95.     

Changes in fecal microbiota and metabolomics in a child with juvenile idiopathic arthritis (JIA) responding to two treatment periods with exclusive enteral nutrition (EEN)

The microbiome and immune system of the digestive tract are highly important in both health and disease. Exclusive enteral nutrition (EEN) is a common anti-inflammatory treatment in children with Crohn’s disease in the European countries, and the mechanism is most likely linked to changes in the intestinal microbiome. In the present study, EEN was given in two treatment periods several months apart to a patient with very severe, disabling juvenile idiopathic arthritis (JIA), with a remarkable clinical response as the result. The aim of the present study was to study how the EEN treatment influenced the microbiome and metabolome of this patient. Fecal samples from before, during, and between treatments with EEN were studied. The microbiome was analyzed by sequencing of 16S rRNA amplicons using Illumina MiSeq, and the metabolome was analyzed using nuclear magnetic resonance. The microbiome changed markedly from treatment with EEN, with a strong reduction of the Bacteroidetes phylum. Metabolic profiles showed clear differences before, during, and between treatment with EEN, where butyrate, propionate, and acetate followed a cyclic pattern with the lowest levels at the end of each treatment period. This patient with JIA showed remarkable clinical improvement after EEN treatment, and we found corresponding changes in both the fecal microbiome and the metabolome. Further studies are needed to explore the pathophysiological role of the intestinal canal in children with JIA.     

Increased expression of CD154 (CD40L) on stimulated T-cells from patients with psoriatic arthritis

OBJECTIVES: CD40L is a costimulatory molecule and an early activation marker of T-lymphocytes. Based on the hypothesis that activated T-cells may play a role in the pathogenesis of psoriatic arthritis (PsA), we evaluated the level of CD40L expression on T-cells from patients with PsA. METHODS: We analysed 12 patients with PsA, six patients with rheumatoid arthritis (RA) and four healthy volunteers. T-cell surface expression of CD40L was evaluated using two-colour flow cytometry in (i) the resting state and (ii) following stimulation with phorbol myristate acetate/ionomycin, with or without ciclosporin (CsA)-mediated inhibition. RESULTS: Expression of CD40L was significantly increased on activated T-cells from patients with PsA, particularly those with active disease, when compared with normal individuals and patients with RA (mean percentages of CD3+ CD40L+ cells: 23.74, 11.59 and 9.57% for patients with active PsA, patients with RA and healthy volunteers, respectively). CsA-mediated inhibition of CD40L induction was equally effective in all study groups. CONCLUSION: CD40L is overexpressed on T-cells from patients with active PsA. This may indicate a role for CD40L in PsA pathogenesis. Larger-scale studies are warranted to address these issues.     

Outcome in adults with juvenile idiopathic arthritis. Comparison of the DUTCH-AIMS2 between JIA and RA

OBJECTIVES: To compare outcome in adult patients with JIA in childhood with outcome in young adults with RA and to evaluate the use of the DUTCH-AIMS2 in adult JIA patients METHODS: A questionnaire containing the DUTCH-AIMS2 to assess health outcomes (answers ranging from 0-10: 0=best) was sent to 142 adults with JIA (18-40 years). These health outcomes were compared with those of 34 young RA patients (< or = 40 years) from former studies. The DUTCH-AIMS2 was tested for its reliability and validity in adult JIA patients. RESULTS: The response rate was 71%. Disease duration of JIA patients (mean 19.2+/-9.5 years) was longer than in young RA patients (mean 7.8+/-5.3 years). RA patients scored worse than JIA patients in all health status areas with the exception of mobility. The mean health outcome scores were low for all groups (< or = 4.80). The internal consistency and the validity of the DUTCH-AIMS2 were satisfactory. CONLUSIONS: Overall, the health outcome of oligoarticular and polyarticular adult JIA and young RA patients was quite good. The DUTCH-AIMS2 can be used as an instrument in outcome studies in JIA patients.     

Burden and cost of illness in patients with juvenile idiopathic arthritis

OBJECTIVE: To estimate the cost of illness in an incidence based cohort of patients with juvenile idiopathic arthritis. METHODS: Direct costs (healthcare and non-healthcare costs) and indirect costs (productivity loss due to sick leave and work disability) were measured in 215 JIA patients, assessed on an average of 17 years after disease onset. Assessment included a clinical evaluation, a structured interview, and two self completion questionnaires. Annual direct costs were estimated based on the reported use of healthcare services and resources, using average unit prices. Indirect costs were estimated from the number of work days missed-that is, using the human capital approach. RESULTS: The mean total cost of late JIA was estimated to be 3500 per patient and year, of which the direct cost contributed more than half. Patients with still active disease (55%) incurred the major share (90%) of the cost. They had a mean total cost of 5700 per patient year, with those under rheumatological care incurring a cost of 9300. Having a certain JIA subgroup, functional disability, or receipt of specialised care independently contributed to the total cost in active JIA. Highest mean total costs were found in active seropositive polyarthritis (17 000) and extended oligoarthritis (11 000), while the lowest were found in active enthesitis related arthritis (1500) and persistent oligoarthritis (2700). CONCLUSIONS: Estimated 12 month costs in late JIA are considerable, differing among the various JIA subgroups. Treatment strategies in JIA should be analysed for their cost effectiveness in the long term.     

Evaluation of plasma microRNA expressions in patients with juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, yet its etiology is unknown. It is known that microribonucleic acids (miRNAs) play a role in immunoregulation. We aimed to evaluate the plasma expression of some candidate miRNAs that are associated with the pathogenesis of autoimmunity. Thirty-one patients diagnosed with JIA and age-sex-matched 31 healthy children were enrolled for the study. The plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204, and miRNA-451), which are known to be associated with autoimmunity, were examined in all the subjects. The plasma levels of miRNAs were measured with real-time PCR in the patients in active and inactive periods and in the healthy controls. The groups were compared with each other. The plasma miRNA-155 levels were found to increase in the JIA patients compared to the healthy controls, and it was statistically more significant in the inactive period. We found that the JIA patients had the higher levels of miRNA-16 and the lower levels of miRNA-204/miRNA-451 expressions compare with the control group, but there was no statistically significant difference. A statistically significant decrease in the plasma levels of miRNA-204 was found in the patients that were in inactive disease with only methotrexate therapy. The plasma miRNA expressions were compared in the JIA subtypes, and it was observed that miRNA-204 levels were higher in polyarticular JIA and miRNA-451 levels were higher in enthesitis-related arthritis without statistical significance. The significant alterations in the plasma expression of miRNA-155 and miRNA-204 suggest to us that these molecules may be related to the pathogenesis of JIA. More comprehensive and functional researches about the role of these molecules are needed in this regard.     

Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis

OBJECTIVE: To determine if anti-cyclic citrullinated peptide antibodies (anti-CCP) can be detected in sera of patients with juvenile idiopathic arthritis (JIA) and if they can be used to identify patients with a more destructive course of disease. METHODS: One hundred serum samples of 71 patients with JIA taken at different time points in their disease course were analyzed by a commercially available anti-CCP ELISA. Followup serum samples from 28 patients were also tested. Correlations between anti-CCP and disease characteristics, medication, and radiological damage (presence of joint space narrowing and/or erosions) were also determined. RESULTS: The serum samples came from patients of all 8 different subtypes of JIA (mean age: 9.6 years, median: 10.5; disease duration mean: 39 months, median: 24) including 11 polyarticular rheumatoid factor positive (IgM-RF) patients. Anti-CCP was positive in 73% of the IgM-RF positive JIA patients and in 3% of the other JIA patients (p < 0.0001). Disease duration, medication, and anti-nuclear antibody positivity did not differ significantly between anti-CCP positive and negative patients. Testing of followup samples showed almost identical anti-CCP results. All IgM-RF positive JIA patients had radiological damage (p < 0.001). Of the anti-CCP positive patients, 80% had radiological damage resulting in a significant difference between anti-CCP positive and negative patients (p = 0.009) with an odds ratio (OR) of 12.7, but corrected for IgM-RF, the OR was no longer significant (p = 0.88). CONCLUSION: Anti-CCP antibodies can be detected in the sera of patients with JIA but almost exclusively in the subset of patients with polyarticular IgM-RF.     

CD28-T细胞亚群在类风湿关节炎患者外周血和关节液中的表达

目的 探讨CD28-T细胞亚群在类风湿关节炎(RA)患者外周血和关节液中的变化和意义。方法 随机选择RA患者45例,取新鲜抗凝外周血单个核细胞(PBMC),其中15例同时提取关节液单个核细胞( SFMC),以流式细胞技术检测CD28-T细胞数量及其表面可诱导共刺激分子(ICOS)的表达。2 组间比较用独立样本t检验。结果 ①与PBMC相比,RA患者SFMC中CD4+CD28+ ICOS+、CD4+CD28-ICOS+、CD8+ CD28+、CD8+ CD28+ ICOS+T细胞明显升高[(36±19)％与(15±8)％,t=-4.234,P＜0.01;(2.1±2.2)％与(0.6±1.4)％,t=-3.143,P＜0.01;(62±15)％与(47±18)％,t=-2.885,P＜0.01;(9±9)％与(3±3)％,t=-2.131,P＜0.05];CD8+CD28-T细胞明显降低[(38±15)％与(54±18)％,t=2.975,P＜0.01];CD8+ CD28- ICOS+、C1D4+CD28+和CD4+CD28-T细胞无明显变化（P＞0.05）。②同一RA患者SFMC与PBMC相比,CD4+CD28+ICOS+、CD8+ CD28+T细胞明显升高[(38±18)％与(16±10)％,t=-4.065,P＜0.01;(61±16)％与(41±21)％,t=-2.883,P＜0.01];CD8+ CD28-T细胞明显降低[(39±16)％与(59±21)％,t=2.949,P＜0.01]。③缓解期与活动期RA患者相比,PBMC中CD4+CD28-、CD8+ CD28-、CD28-ICOS+T细胞无明显变化（P＞0.05）。结论 RA患者关节液中CD28-T细胞亚群失衡和ICOS分子表达异常,可能是导致RA关节损伤的重要机制。