OBJECTIVE: To assess the current International League of Associations for Rheumatology (ILAR) classification criteria (Edmonton, 2001) for juvenile idiopathic arthritis (JIA) in Indian patients. METHODS: Out of 441 children, 330 with chronic joint pains were diagnosed with juvenile onset chronic inflammatory arthritis and followed in an observational cohort. Our study was carried out from 1994 to 2006 in a community rheumatology clinic. Emphasis was placed on obtaining data required by the ILAR system. Of the original group, 235 children were eventually classified as having JIA; 108 were examined during the first year of illness. RESULTS: We assigned 224 children (95%) to discrete JIA categories: enthesitis-related arthritis (ERA; 36%), oligoarthritis (OLA-persistent; 17%), polyarthritis rheumatoid factor (RF)-negative (17%), polyarthritis RF-positive (12%), systemic arthritis (8%), OLA-extended (4%), and psoriatic arthritis (1%). The remaining 11 children (5%) were classified with undifferentiated arthritis (mostly an overlap due to seropositive RF and/or HLA-B27). The prevalence of ERA (89% HLA-B27-positive) and seropositive RF was unexpectedly high. Although agreement (kappa > 0.79) with the American College of Rheumatology criteria and the European Spondylarthropathy Study Group criteria was good to excellent, the ILAR system was found to be more comprehensive and clinically homogeneous. However, some problems appear unique in our scenario. CONCLUSION: A wide-spectrum phenotype of JIA is demonstrated by an Indian cohort. Although useful, RF and HLA-B27 in this population proved problematic to the ILAR classification.

Abstract The purpose of the present study was to investigate the incidence of juvenile rheumatoid arthritis (JRA) among Japanese children and to evaluate the clinical features of this disease. A questionnaire was sent to the department of pediatrics of 1290 hospitals in Japan, in 1994, asking for the number of rheumatic patients during the past 10 years. Subsequently, a second questionnaire was sent asking for the type of onset, clinical features, treatment, and other details. The results of 570 cases were obtained. Of these, 310 cases (54%) were the systemic onset type, 140 cases were the polyarticular onset type (25%), and 120 cases (21%) were the pauciarticular onset type. Hence, in the present series of children, the proportion of the pauciarticular type was less than the other two types of JRA. In the laboratory findings of the systemic onset type, hyperferritinemia and thrombocytosis were noted, in addition to leukocytosis, positive C-reactive protein (CRP) and accentuated erythrocyte sedimentation rate (ESR). The rheumatoid factor was positive in 50% of patients with the polyarticular onset type. Chronic uveitis was recognized in 13 cases (10.8%) of the pauciarticular onset type. In four girls, uveitis started before the onset of arthritis. Nonsteroidal anti-inflammatory drugs were used in almost one-third of cases, and methotrexate (MTX) was used in 12.8% of cases. The quality of life of children with JRA was disturbed in almost 20% of cases. Therefore, for the early and definitive diagnosis of the systemic type of JRA, diagnostic procedures including thrombocyte counts and serum ferritin level, should be performed. In order to obtain good results and to avoid side effects, a protocol for the use of disease modifying anti-rheumatic drugs and immunosuppressants, especially for the use of MTX, must be established.

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Abstract Top of page Abstract PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES Objective To address the functional and prognostic relevance of the 鈭173 single-nucleotide G-to-C polymorphism of the macrophage migration inhibitory factor (MIF) gene in patients with systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) by evaluating its association with serum and synovial fluid levels of MIF, with glucocorticoid requirement, and with the outcome of the disease. Methods A total of 136 patients with systemic-onset JIA were studied, including 98 patients from the British Paediatric Rheumatology Study Group's National Repository for JIA and 38 patients who were followed up at the IRCCS Policlinico San Matteo (Pavia, Italy) and the IRCCS G. Gaslini (Genoa, Italy). The MIF-173 polymorphism was genotyped using SnaPshot ddNTP primer extension and capillary electrophoresis. MIF levels were measured by enzyme-linked immunosorbent assay. The evaluation of the association of the MIF-173 polymorphism with outcome was performed only in Italian patients who were followed up for >5 years, by analyzing retrospectively 1) the number of joints with active arthritis and the number of joints with limited range of motion; 2) the score, at the last visit, on the Italian version of the Childhood Health Assessment Questionnaire (C-HAQ); and 3) data concerning the treatment regimens during the disease course. Results Systemic-onset JIA patients carrying a MIF-173*C allele had serum and synovial fluid levels of MIF significantly higher than those in patients with the GG genotype. The duration of glucocorticoid treatment on a daily regimen was significantly longer in patients carrying a MIF-173*C allele than in MIF-173 GG homozygous patients. Moreover, the duration of clinical response to intraarticular injection of triamcinolone hexacetonide was significantly shorter in patients carrying a MIF-173*C allele. At the last visit, the numbers of joints with active arthritis, the C-HAQ scores, and the numbers of joints with limited range of motion were significantly higher in patients carrying the MIF-173*C allele. Conclusion Our study shows the functional relevance of the MIF-173 polymorphism and suggests that the MIF-173*C allele is a predictor of poor outcome in systemic-onset JIA.

Abstract Top of page Abstract PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES Objective To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA). Methods Three hundred twenty-one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. Results MIF was linked and associated with JIA ( P = 0.0016). Specifically, a 2-point promoter haplotype, CATT 7 鈥揗IF-173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF-173*G/C was found to be specific to the cell type. Conclusion Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated.

Abstract Top of page Abstract PATIENTS AND METHODS RESULTS DISCUSSION Acknowledgements REFERENCES Objective Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case–control study, a significant association between the IL-6 61174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 61174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A n T n tract in the promoter. Methods We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the 61174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A n T n tract at 61392 to 61373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus. Results There was a significant excess transmission of the 61174G allele in the systemic JIA families ( P = 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years ( P = 0.007). No significant association with the other subtypes was found. No A n T n alleles or 61174/A n T n haplotypes were significantly associated with systemic JIA. Conclusion This study confirms that the IL-6 –174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset ≤5 years suggests that there may be genetic heterogeneity between the 2 groups.

To determine the prevalence of human parvovirus B19 infection in patients with juvenile idiopathic arthritis (JIA) by detection of specific IgM, IgG, and viral DNA.Serum samples of 50 patients with diagnosis of JIA and 39 healthy controls were analyzed by ELISA to detect IgG and IgM anti-B19-specific antibodies. The parvovirus B19 genome was detected by nested polymerase chain reaction (PCR). The average age of the patients was 9.6 years (2-14 yrs); 30 were female (60%) and 20 male (40%). The definitive diagnoses of these patients corresponded to 19 systemic forms (38%), 11 to the oligoarticular variety (22%) and 20 to the polyarticular (40%). The average age of the control group was 7.8 years (2-16 yrs); the distribution by sex was 25 females (64%) and 14 males (36%).IgM against parvovirus B19 was detected in 20% of the cases (10 patients) and B19 DNA genome by PCR in 48% (24 patients); in 10% of the cases (5 patients), both markers were detected. IgG was found in 32% (16 patients). In the control group neither IgM nor the viral genome was detected. However, 43.5% of the controls (17/39) had IgG against parvovirus B19, indicating past infection by the virus.Our study confirms recent observations regarding a high prevalence of viral DNA in JIA patients and a possible role of this viral infection in JIA pathogenesis.

An 11-year-old female patient, whose systemic type (JIA) had maintained in remission for the previous 4 years while taking only a small amounts of , showed an abrupt 2nd relapse with five days after receiving a live-attenuated vaccine, which was a primary immunization. Her serum levels of anti-IgM and IgG increased, and her laboratory findings such as a , elevated serum levels of CRP, and other inflammatory cytokine profiles were similar to the findings observed during her previous JIA active stage. After being administration of co-therapy with steroid pulse, , and phosphodiesterase inhibitor gradually improved her clinical symptoms such as spiky fever, and arthralgia. Her intermittent fever and increased serum levels of CRP and , however, have been sustained for more than 2 years, and this prolonged active clinical course therefore differed from her previous JIA active stage.This abrupt relapse only five days after vaccination was suggested not to be directly related with , but instead to be related with the molecular between and JIA.

Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators.To identify a panel of cytokines specifically related to the inflammatory process in JIA.Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease.Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor alpha, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested.It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

We measured interleukin-6 (IL-6) levels in 70 serum samples obtained from 25 patients with systemic-onset juvenile rheumatoid arthritis (JRA), using the hybridoma cell line B9. Patients with systemic-onset JRA had significantly elevated serum IL-6 levels during active disease (mean +/- SD 92.1 +/- 75.1 hybridoma growth factor units/ml; P less than 0.00001 versus healthy age-matched controls), but not during remission. Serum IL-6 levels correlated with the extent and severity of joint involvement (P less than 0.001) and with platelet counts (P less than 0.05). Our data suggest that IL-6 plays a significant role in the pathogenesis of systemic-onset JRA.

Abstract Top of page Abstract PATIENTS AND METHODS RESULTS DISCUSSION Acknowledgements REFERENCES Objective To analyze which cellular compartments are involved in the initial phase of systemic-onset juvenile rheumatoid arthritis (JRA), and to investigate the role that myeloid-related protein 8 (MRP-8) and MRP-14, two S-100 proteins that are primarily expressed in phagocytes, play in the disease. Methods Skin biopsy samples obtained during patients' acute episodes of systemic-onset JRA were analyzed by immunohistochemistry and in situ hybridization. Concentrations of MRP-8/MRP-14 in serum were determined by enzyme-linked immunosorbent assay. Results By analyzing biopsy samples from cutaneous rashes during the initial phase of systemic-onset JRA, we discovered infiltration of leukocytes expressing MRP-8 and MRP-14. Surprisingly, keratinocytes also showed de novo synthesis of these proinflammatory proteins, indicating activation of epithelial cells during systemic-onset JRA. Serum concentrations of MRP-8/MRP-14 were 120-fold higher compared with healthy controls and 鈭12-fold higher compared with patients with other inflammatory diseases. Concentrations of MRP-8/MRP-14 in patients with systemic-onset JRA fell dramatically after remission was induced. Conclusion The exceptionally high serum levels of MRP-8 and MRP-14 in active systemic-onset JRA make them prime candidates as markers for monitoring disease activity and response to treatment. Since MRP-8/MRP-14 exhibit direct effects on leukocyte adhesion to the vascular endothelium, their extensive expression in the epidermis indicates an active role for these S-100 proteins in the initial phase of this systemic autoimmune disease.

Myeloid-related protein (MRP) 8 and MRP14, two members of the S100 family expressed in myelomonocytic cells, have been ascribed some extracellular functions, e.g. antimicrobial, cytostatic, and chemotactic activities. Since S100 proteins lack structural requirements for secretion via the classical endoplasmic reticulum/Golgi route, the process of secretion is unclear. We now demonstrate the specific, energy-dependent release of MRP8 and MRP14 by human monocytes after activation of protein kinase C. This secretory process is not blocked by inhibitors of vesicular traffic through the endoplasmic reticulum and Golgi, and comparative studies on tumor necrosis factor-alpha and interleukin-1beta indicate that MRP8 and MRP14 follow neither the classical nor the interleukin-1-like alternative route of secretion. Inhibition by microtubule-depolymerizing agents revealed that MRP8/MRP14 secretion requires an intact tubulin network. Accordingly, upon initiation of MRP8/MRP14 secretion, immunofluorescence microscopy showed a co-localization of both proteins with tubulin filaments. Release of MRP8 and MRP14 is associated with down-regulation of their de novo synthesis, suggesting that extracellular signaling via MRP8/MRP14 is restricted to distinct differentiation stages of monocytes. Our data provide evidence that the S100 proteins MRP8 and MRP14 are secreted after activation of protein kinase C via a novel pathway requiring an intact microtubule network.

Systemic onset juvenile idiopathic arthritis (SoJIA) encompasses approximately 10% of cases of arthritis that begin in childhood. The disease is unique in terms of clinical manifestations, severity of joint involvement, and lack of response to tumor necrosis factor blockade. Here, we show that serum from SoJIA patients induces the transcription of innate immunity genes, including interleukin (IL)-1 in healthy peripheral blood mononuclear cells (PBMCs). Upon activation, SoJIA PBMCs release large amounts of IL-1beta. We administered recombinant IL-1 receptor antagonist to nine SoJIA patients who were refractory to other therapies. Complete remission was obtained in seven out of nine patients and a partial response was obtained in the other two patients. We conclude that IL-1 is a major mediator of the inflammatory cascade that underlies SoJIA and that this cytokine represents a target for therapy in this disease.

To evaluate quantitative or qualitative differences in synovial fluid (SF) cytokine levels among patients with systemic juvenile rheumatoid arthritis (JRA), antinuclear antibody positive pauciarticular JRA, or adult RA.SF levels of interleukin 1alpha (IL-1alpha), IL-1beta, IL-1 receptor antagonist (IL-1Ra) IL-11, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), leukemia inhibitory factor (LIF), all measured by immunoassays, and of IL-6, measured with a bioassay using B9 cells, were evaluated in 11 patients with systemic JRA, 24 with pauciarticular JRA, and 22 adult patients with RA.SF IL-6 levels were significantly higher in patients with systemic JRA than patients with pauciarticular JRA (p = 0.003) or RA (p = 0.002). IL-1alpha was detectable in 12/24 SF samples from pauciarticular JRA, in 2/22 SF from RA, and in no sample from systemic JRA (p = 0.004 vs RA; p = 0.005 vs systemic JRA). SF IL-11 levels were significantly higher in patients with RA than patients with systemic JRA (p = 0.012) or pauciarticular JRA (p = 0.005). We found no significant differences in SF levels of IL-1beta, IL-1Ra, TNF-alpha, sTNFR1, or LIF.In systemic JRA, SF levels of IL-6 are significantly higher than in pauciarticular JRA or in RA; IL-1alpha is present in a significant proportion of patients with pauciarticular JRA, but not in those with RA or systemic JRA.

<h2 class="secHeading" id="section_abstract">Abstract</h2><p id="simple-para0010">Interleukin-6 (IL-6) is a cytokine that can facilitate autoimmune phenomena, amplify acute inflammation and promote the evolution into a chronic inflammatory state. In addition, it is a major promoter of bone resorption in pathological conditions. In particular, IL-6 has a pivotal role in synovitis, bone erosions and in the systemic features of inflammation. This cytokine specifically binds to IL-6 receptor (IL-6R), forming the IL-6/IL-6R complex that binds to gp130, a membrane-bound protein, which is involved in non-ligand-binding signal transduction. Targeting IL-6R in both animal models of arthritis and in rheumatoid arthritis patients with a humanized anti IL-6R monoclonal antibody (tocilizumab) effectively controls local and systemic inflammatory manifestations and blocks cartilage and bone destruction. Given the pleiotropic function of IL-6 it can be anticipated that other inflammatory diseases and bone metabolic conditions might benefit from selective IL-6 signaling inhibition.</p>

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To characterize the initial clinical and laboratory features of patients with systemic onset juvenile rheumatoid arthritis (soJRA) through a Web-based registry.Patients diagnosed with soJRA in the last 15 years at 3 medical centers in Pennsylvania were identified. Data were collected retrospectively using a Web-based interface in compliance with patient privacy standards. Inferential statistics were used to compare features of patients with and without macrophage activation syndrome.We identified 136 patients; 88% of patients presented with arthritis (8% mono-, 45% oligo-, 47% polyarticular). The most common joints involved were the knee (68% of patients with arthritis), wrist (68%), and ankle (57%). The International League of Associations for Rheumatology criteria for systemic juvenile idiopathic arthritis (SJIA) identified only 30% of patients at presentation.We successfully characterized the presenting features of a relatively rare disease, soJRA, through the use of a Web-based registry. Current classification criteria for SJIA may not be particularly sensitive for diagnosis at presentation.

Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease.Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset.In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003).Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.

ABSTRACT Although the basic ingredients to produce heavy precipitation are universal, the local concatenation of these ingredients - manifested in the dominant patterns of rainfall organization - appears to differ from one region to another. To investigate how heavy precipitation is organized differently in the northeastern United States as compared to the more extensively studied midwestern U.S., we examined 148 events in the northeastern U.S. during the warm seasons of the years 2003-2007. Events were selected from flash flood reports in NOAA's Storm Data publication. To focus on mid-latitude processes, events due to named tropical systems and their remnants were excluded. We classified the events based on the patterns of rainfall as exhibited in radar reflectivity and diagnosed their atmospheric conditions using the North American Regional Reanalysis and surface and upper air observations. The dominant rainfall patterns for the events in this study exhibit a dichotomy between strongly and weakly organized events. The mode of rainfall organization that occurred most frequently (28 events) was that of scattered precipitation, often peppered within the warm sector of a mid-latitude cyclone. Heavy precipitation under this scenario was a result of several of these scattered cells or lines of convection traversing the same area. These events lacked a prevalent synoptic or mesoscale forcing mechanism to focus the precipitation, so the means of organization for these events were more subtle. This high frequency of weakly organized events appears to distinguish the northeastern U.S. from the midwestern U.S., where more organized mesoscale convective systems are the dominant mode of heavy precipitation. Nearly as common (26 events) were back-building events, in which precipitation was sustained by the regeneration of convection lifted by storm-scale cold outflow. This pattern typically produced higher basin-scale rainfall accumulations than the other common modes of convection identified in this study. Two of the events among the largest precipitation totals, one of which generated local rainfall observations of >250 mm in less than six hours, exhibited a common pattern of back-building cells which remained quasi-stationary as a convective line of precipitation approached. Although this scenario is relatively rare, it is significant for real-time forecasting applications, as the key components - a low-level localized area of convergence in the back-building location and a narrow, elongated region of enhanced moisture throughout most of the depth of the troposphere associated with the convective line - are in place before the precipitation pattern develops and hence may provide the opportunity for early warning.

Abstract Objective To examine the ability of a previously described set of criteria to predict poor functional outcome in a large, multicenter cohort of children with systemic-onset juvenile rheumatoid arthritis (JRA). Methods All children who were diagnosed with systemic-onset JRA since 1980 at the Hospital for Sick Children (Toronto), since 1983 at the Isaac Walton Killam Hospital for Children (Halifax), and since 1981 at the Children's Hospital of Eastern Ontario (Ottawa) were evaluated. Patients were included in the study if they had been evaluated clinically within 6 months of diagnosis and had been followed up for at least 2 years. Patients were divided into 4 cohorts according to their length of followup: 2–4 years, 4–7 years, 7–10 years, and >10 years. Using previously described criteria for destructive arthritis in children with systemic-onset JRA, the patients were classified as either high risk or low risk for poor functional outcome based on the data from their 6-month visit. High-risk patients had active systemic disease (persistent fever or corticosteroid requirement for control of systemic disease) and a platelet count ≥600 × 10 9 /liter. Poor outcome was defined as moderate or severe disability (defined as a score of ≥0.75 on the Childhood Health Assessment Questionnaire) or disease-associated death. Results Among 122 eligible patients with systemic-onset JRA, we were able to contact 111 (91%) for outcome data. The mean followup period was 7.7 years (SD 3.7). The mean age at outcome assessment was 13.5 years (SD 5.3). There were 51 boys and 60 girls. Twenty-four patients (22%) had moderate-to-severe disability and 2 patients died; these 26 patients were considered to have had a poor outcome. We could determine risk classification for 104 patients. Twenty-four patients (23%) met the criteria for high risk at the 6-month visit. Overall, the risk of a poor functional outcome was significantly higher in the high-risk group (relative risk 3.3, 95% confidence interval [95% CI] 1.73–6.43, P = 0.0004). This risk was most marked in the cohort with >10 years of followup (relative risk 4.3, 95% CI 1.82–10.29, P = 0.006). Conclusion The presence of active systemic disease at 6 months, as characterized by fever or the need for corticosteroids, and thrombocytosis strongly predicted the development of a poor functional outcome in these patients. This was especially apparent with long-term followup. Our study validates the previously developed prognostic criteria for systemic-onset JRA.

pGuidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are02intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.br /The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances./ppGuidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any02specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice./ppThe American College of Rheumatology is an independent, professional, medical and scientific society which does02not guarantee, warrant, or endorse any commercial product or service./p

Kretzschmar R, Meyer HJ, Teschendorf HJ, Z02llner B.

Objectives To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).<br/>Methods A multicentre, randomised, double-blind, placebo-controlled trial was conducted. The primary objective was to compare the efficacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA. Response was defined by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline. After month 1 (M1), patients taking placebo were switched to anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months, and analyses of treatment effect on blood gene expression profiling.<br/>Results At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003). Ten patients from the placebo group switched to anakinra; nine were responders at M2. Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of efficacy (n=2) or a disease flare (n=2). Blood gene expression profiling at enrolment and at 6 months' follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra.<br/>Conclusions Anakinra treatment is effective in SJIA, at least in the short term. It is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature.

Objective. To conduct a prospective cohort study using anakinra, a recombinant IL-1 receptor antagonist (IL-1Ra), as first-line therapy in patients with new-onset systemic juvenile idiopathic arthritis (JIA).<br/>Methods. Therapy with recombinant IL-1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically. The protocol contained a stop strategy for patients who met at least the adapted American College of Rheumatology 90% criteria for improvement in JIA (ACR Pediatric 90 [ACR Pedi 90]) after 3 months.<br/>Results. We included consecutive patients with new-onset systemic JIA. The mean followup period was 32 months (range 12-54 months). At the 3-month time point, 85% of the patients showed an adapted ACR Pedi 90 response or had inactive disease; 75% of the patients achieved this response while receiving recombinant IL-1Ra alone. After 1 year, 17 of the 20 patients met the criteria for clinically inactive disease, and 13 of these patients met these criteria while receiving monotherapy with recombinant IL-1Ra. However, because of persistent disease activity, 7 of the 20 patients required additional therapy besides recombinant IL-1Ra. According to our stop strategy, 73% of patients with at least an adapted ACR Pedi 90 response at 3 months could stop recombinant IL-1Ra treatment within 1 year. After 2 years, 12 (86%) of 14 patients met the criteria for disease remission, either while receiving (n = 4) or not receiving (n = 8) medication. After 3 years, 10 (91%) of 11 patients met the criteria for disease remission, either while receiving (n = 2) or not receiving (n = 8) medication.<br/>Conclusion. This is the first prospective study in which recombinant IL-1Ra was used as first-line therapy in patients with systemic JIA. We observed excellent responses in nearly all patients within 3 months. In the majority of responding patients, treatment with recombinant IL-1Ra could be stopped within 1 year, with remission being preserved during followup. In approximately one-third of patients, concomitant therapy was required for maintenance of clinical response.

To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemic-onset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.

Abstract OBJECTIVE: To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. RESULTS: Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed. CONCLUSION: Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated. Copyright 2013 by the American College of Rheumatology.

Objective. To assess the frequency of clinical remission in a cohort of patients with systemic juvenile idiopathic arthritis (JIA) who received continuous anti-tumor necrosis factor (TNF) therapy; and to identify potential predictors of remission. Methods. Patients with systemic JIA who were treated with anti-TNF agents for > 6 months were studied. Demographic and nosologic variables recorded at the start of anti-TNF therapy were analyzed. Association between early variables and occurrence of remission was evaluated through Cox proportional hazard regression analysis. Results. Forty-five patients were included (30 girls), median age 9 years (range 2-17 yrs), age at disease onset 5 years (range 0.5-15), disease duration 3 years (range 0.5-13). Twenty-one (47%) children showed systemic symptoms at the start of anti-TNF therapy. Patients received therapy for 24 months (range 6-88): 45 (100%) were given etanercept, 17 (38%) infliximab, and 5 (11%) adalimumab, in combination with methotrexate. Anti-TNF switching was performed in 22 (49%) children. Eleven (24%) met definition criteria for remission while taking etanercept (n = 8), infliximab (2), or adalimumnab (1). Remission occurred following 26 (range 9-65) months of therapy. Flares Occurred in 5 (45%) patients 2 to 14 months after remission was first recorded. Absence of systemic symptoms at the start of therapy and fulfilment of improvement criteria at Month 3 were associated with remission in Univariate analysis; no variable showed any association in multivariate analysis. Conclusion. Twenty-four percent of patients with systemic JIA experienced remission with anti-TNF therapy, but only 13% experienced Sustained benefit. (First Release April 1 2009; J Rheumatol 2009;36:1078-82; doi: 10.3899/jrheum.090952)