Systemic-onset Juvenile Idiopathic Arthritis Research Articles

Assessment of vascular function in systemic onset juvenile idiopathic arthritis.

An increased incidence of cardiovascular disease has been found in rheumatic disorders. Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Prolonged immunological inflammatory process leads these patients to an early onset of atherosclerosis. We aimed to assess the presence of early vascular dysfunction in patients with systemic onset juvenile idiopathic arthritis (sJIA) and investigate the role of therapy sJIA in vascular health. Thirty-three patients (22 males, 11 females) diagnosed with sJIA according to the International League of Associations for Rheumatology criteria were compared to 72 age- and sex-matched controls. None of the participants was overweight, obese, or had a history of hypertension, dyslipidemia, diabetes mellitus, or cardiovascular disease. Arterial stiffness (As) was evaluated by measurement of carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) with a Vicorder. The mean age of patients in this study was 9.96 ± 3.71years (range 4-16years) and the mean age of controls was 10.9 ± 3.52years (range 4-19years). These two groups were well matched for age, sex, and BMI. The mean age of patients at the onset of disease was 7.06 ± 3.9years (range 3-15years). The mean duration of disease and active disease was 79 ± 45months (range 6-162months) and 58 ± 49months (range 1-101months), respectively. The highest levels of PWV and AIx were found in the patient group. Seven patients had had macrophage activation syndrome at presentation. In these patients, vascular changes were higher than other patients (6.30 ± 0.42m/s vs 5.17 ± 0.55m/s, p = 0.01, respectively). The corticosteroid therapy was found associated with higher PWV, (p < 0.05), while there was no difference between vascular parameters and use of non-steroid therapies (methotrexate (MTX), anti-TNF alfa agents). We also find statistically significant correlation between PWV and disease duration (p = 0.003, r = 0.45). Vascular function is impaired in patients with sJIA at a very young age. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications).

Arthrite juvénile idiopathique : définition et classification

Juvenile idiopathic arthritis (JIA) is a group of diseases defined by the presence of arthritis of more than 6weeks duration in patients aged less than 16years and with unknown etiology. The international classification based on clinical and biological criteria define each type of JIA: systemic, oligoarticular, polyarticular with and without rheumatoid factor, enthesitis-related arthritis, and psoriatic arthritis. However, some discussions persist concerning systemic-onset juvenile idiopathic arthritis, whose clinical symptoms and pathogenic mechanisms are quite similar to those observed in autoinflammatory diseases, arthritis with antinuclear factors (poly- and oligoarticular) that could be considered as a homogenous group, and a family history of psoriasis that frequently led to unclassified arthritis. Better knowledge of the pathogenic mechanisms should improve the initial clinical classification with more homogeneous groups of patients and reduce the number of unclassified cases of arthritis.

Macrophage activation syndrome in a patient with systemic onset of the juvenile idiopathic arthritis.

Systemic onset juvenile idiopathic arthritis (sJIA) is defined as arthritis affecting one or more joint usually in the juvenile age group (< 16 years of age) with or preceded by fever of at least 2 weeks duration that is documented to be daily (“quotidian”) for at least 3 days which may be associated with evanescent (non-fixed) erythematous rash or generalized lymph node enlargement or hepatomegaly/splenomegaly/both or serositis. Macrophage activation syndrome (MAS) is a life-threatening complication of sJIA marked by sudden onset of non-remitting high fever, profound depression in all three blood cell lines (i.e. leukopenia, anemia, and thrombocytopenia), hepatosplenomegaly, lymphadenopathy, and elevated serum liver enzyme levels. In children with systemic juvenile idiopathic arthritis, the clinical picture may mimic sepsis or an exacerbation of the underlying disease.We report a case of a 16-year-old female patient presenting with high grade fever with joint pains and generalized weakness which proved to be systemic onset juvenile idiopathic arthritis with macrophage activation syndrome after ruling out all other differential diagnoses and responded well to intravenous steroids.

Atypical Cutaneous Manifestations in Adult Onset Still's Disease.

Adult Onset Still's Disease (AOSD), an adult variant of systemic onset juvenile idiopathic arthritis, is a rare systemic inflammatory disorder of unknown aetiology. The rarity of this disease is associated with low index of suspicion and delayed diagnosis in patients suffering from it and in the presence of atypical features the diagnosis can be further challenging. This is a case report on a 24-year-old woman, who was a diagnostic dilemma for 2 years due to the nonspecific symptoms of recurrent fever, generalized maculopapular persistent pruritic and tender rash, and polyarthralgia. She was initially diagnosed as leukocytoclastic vasculitis on a skin biopsy and was managed by a dermatologist with various medications including NSAIDs, hydroxychloroquine, dapsone, colchicine, cyclosporine, and high doses of oral steroids with minimal response. Subsequently, she has had multiple admissions with similar symptoms with raised inflammatory markers and negative septic workup. On one occasion, her iron study revealed hyperferritinaemia which led to the suspicion of AOSD. Once the rheumatic fever and infectious, malignant, autoimmune, and lymphoproliferative disorders were excluded, she was diagnosed as probable AOSD and managed successfully with IL-1 (interleukin-1) receptor antagonist, Anakinra, with remarkable and lasting response both clinically and biochemically.

The Pattern of Juvenile Idiopathic Arthritis in a Single Tertiary Center in Saudi Arabia.

Introduction. Juvenile Idiopathic Arthritis (JIA) is the most common chronic arthritis in children. Our aim is to describe demographic, clinical, and laboratory characteristics and treatment of JIA patients followed up in Pediatric Rheumatology clinic in a tertiary center in Saudi Arabia. Methods. Medical records of all patients who are followed up between January 2007 and January 2015 were retrospectively reviewed. Data were collected about demographic, clinical, and laboratory features and treatment. Results. Total patients were 82, males were 31 (37.8%), and mean age of JIA onset was 7.1 ± 3.6 yr. Mean follow-up duration was 2.67±1.6 yr. Systemic onset JIA (SoJIA) was the commonest (36.5%), followed by polyarticular in 29.2% and oligoarticular in 28%. Large and small joints are involved in 76 (92%) and 30 (36.6%), respectively. Main extra-articular feature was fever in 34 (41.4%). Uveitis was diagnosed in 7 (8.5%) and in 5 (21.7%) of oligoarticular JIA. Anemia was found in 49 (59.7%), high ESR in 45 (54.8%), and leukocytosis and thrombocytosis in 33 (40.2%). Positive ANA was found in 30 (36.5%) mainly in oligoarticular subtype as 12 (52%) patients (out of 23) had this positive test. 9 patients (10.9%) required NSAIDs only, 6 patients (7.3%) required NSAIDs and intra-articular steroids only, and 19 (23%) required NSAIDs, methotrexate, steroids, and biologics. Conclusion. SoJIA is the most common JIA subtype in our study. A population based rather than a single center study will give more details about JIA characteristics in Saudi Arabia

Potential Effects of Interleukins on the Pathogenesis of Systemic Onset Juvenile Idiopathic Arthritis

To analyze the correlation of cytokines with clinical inflammatory indexes in systemic onset juvenile idiopathic arthritis (SOJIA). A total of 30 active SOJIAs, 30 remission SOJIAs, and 20 normal controls were enrolled. The clinical inflammatory indexes such as tender joints counts, swelling joints counts, C-reactive protein, erythrocyte sedimentation rate, visual analogue scale (VAS), and disease activity score 28 (DAS28) were detected. The serum cytokines interleukin (IL)-17, IL-6, IL-21, interferon (IFN)-γ, and IL-4 levels were determined with enzyme-linked immunosorbent assay method. The correlation coefficients between these cytokines and two clinical indexes (VAS and DAS28) in the active SOJIA group were calculated with the Spearman's method. The serum IL-17 and IL-6 levels in active SOJIA group were significantly increased compared with those in the remission SOJIA group and control group (p<0.05), and the serum IL-21, IFN-γ, and IL-4 levels showed no obvious difference. In the active SOJIA group, the Spearman coefficients between IL-17 and DAS28, IL-17 and IL-6, IL-6 and DAS28, and between IL-17 and VAS were 0.686 (p=0.000), 0.833 (p=0.000), 0.633 (p=0.000), and 0.524 (p=0.003), respectively. There was no correlation between cytokines of IL-21, IFN-γ, and IL-4 and the clinical indexes of DAS28 and VAS. Furthermore, in the other two groups, none of the five cytokines exhibited an association with DAS28 or VAS. IL-6 and IL-17 were significantly correlated with DAS28 and VAS, and they might be considered as therapeutic targets for the treatment of SOJIA.

IL-6 Blockers in Systemic Onset Juvenile Idiopathic Arthritis

IL-6 has a key role in the pathogenesis, clinical manifestations and activity of Systemic Onset Idiopathic Arthritis (sJIA). Tocilizumab (TCZ), the first humanized antihuman IL-6 receptor antibody, inhibits the activity of IL-6. In this review, we summarize the main studies performed, to date, about the use of TCZ in children affected by sJIA refractory to conventional treatment. Nowadays TCZ can be used, alone or in association with Metotrexate, in children older than 2 years. Its use in children younger than 2 years is being investigated. Further study about its use in sJIA and other type of idiopathic arthritis should be done.

The majority of newly diagnosed patients with juvenile idiopathic arthritis reach an inactive disease state within the first year of specialised care: data from a German inception cohort

ObjectiveTo describe the disease characteristics of patients with juvenile idiopathic arthritis (JIA) included in an inception cohort, to analyse how many patients from each JIA category reach an inactive disease...

A safety evaluation of canakinumab for the treatment of systemic onset juvenile idiopathic arthritis

Introduction: Interleukin-1 (IL-1) is the key molecule of a strong pro-inflammatory pathway in the innate immune system. The IL-1 family harbors components with pro- and anti-inflammatory effects essential for the regulation of the inflammation process. Auto-inflammatory diseases and systemic onset juvenile idiopathic arthritis (JIA) are examples of chronic inflammatory diseases that are IL-1 dependent. IL-1 blockade has proven to be very effective and has greatly improved the outcome of these disorders.Areas covered: This review describes the components of the IL-1 family and the available IL-1 blocking agents for clinical practice. Among them, canakinumab was more recently introduced. Based on the published clinical trials one can conclude that the clinical efficacy in auto-inflammatory diseases is at least as good as other IL-1 blocking agents. The safety data are limited to those registration studies (Phase 2 and 3). In short term the adverse events described are not very different from the other IL-1 blockers.Expert opinion: Longer term use in larger numbers of patients and adequate data collection using large-scale registries are necessary to provide us with a well-balanced overview of safety issues of canakinumab. Registration studies and open label extension studies show an acceptable safety profile so far.

Turkish Pediatric Rheumatology Society consensus statements on systemic onset juvenile idiopathic arthritis in Turkey

Methods Recommendations were established via consensus by a panel of experts in pediatric rheumatology, based on analysis of available scientific evidence obtained from the clinical experience of panelists. The Delphi method solicits the opinion of an expert panel through a carefully designed questionnaire which in this case included questions on: epidemiology, diagnosis, treatment of symptoms, drug choice, adverse events, follow-up visits, hospital and emergency service admissions. The responses were analyzed and discussed in a face to face meeting followed by consensus building steps.

Monocytes and neutrophils in the inflammatory cascade of systemic onset Juvenile Idiopathic Arthritis

8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases

Role of polymorphonucleates in the pathogenesis of systemic juvenile idiopathic arthritis and Still's disease: a proof of concept study

Background Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still9s disease (AOSD) are autoinflammatory disorders characterized by neutrophilia and abnormal innate immunity response [1]. It has been hypothesized a pathogenic role of neutrophils, because of patients neutrophilia, maybe related to the typical higher production of pro-inflammatory cytokines, like IL-1β, whose role in these disorders should explain the efficacy of IL-1 blockers [2, 3]. IL-1β is synthesized as inactive form and its activation is mediated by the NLRP3 inflammasome [4]. Increased release of this cytokine in the extracellular environment lead to a positive feedback loop that perpetuates and amplifies itself stimulation [5]. This mechanism as well as neutrophils9 activation state could be modified in sJIA and AOSD. Objectives Our aim was to verify possible differences between sJIA and Still9s patients compared to healthy donors, in term of PMNs responsiveness to the extracellular environment and activation state. Methods PMNs were obtained from heparinised venous blood of sJIA patients (n=6), AOSD patients (n=4) and healthy controls (HC, n=8). All patients9 samples were collected during stages of active or non-active disease, according to international disease activity criteria used for the assessment of each disease. After lipopolysaccharide (LPS) treatment, IL-1β content in PMNs supernatants was measured by ELISA assay. CD11b expression levels were measured by flow cytometry, together with intracellular ROS levels through the H 2 DCFDA ROS-indicator. Results In comparison with HC, sJIA PMNs showed an increased IL-1β secretion after LPS stimulation (p Conclusions Data from our proof of concepts study suggest a possible involvement of PMNs in the pathogenesis of sJIA and AOSD, since they seem more active respect healthy ones and more sensitive to pro-inflammatory stimuli. Although further studies are necessary to confirm and validate this hypothesis, the trend observed may have a potential role in the direction of future therapeutic studies. References Pay, S., et al., A multicenter study of patients with adult-onset Still9s disease compared with systemic juvenile idiopathic arthritis. Clin Rheumatol, 2006. 25(5): p. 639-44. Mellins, E.D., et al., Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol, 2011. 7(7): p. 416-26. Mavragani, C.P., et al., Adult-Onset Still9s Disease: From Pathophysiology to Targeted Therapies. Int J Inflam, 2012. 2012: p. 879020. Martinon, F., et al., The inflammasomes: guardians of the body. Annu Rev Immunol, 2009. 27: p. 229-65. Frosch, M., et al., The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum, 2009. 60(3): p. 883-91. Disclosure of Interest None declared

A family carrying a homozygous LACC1 truncated mutation expands the clinical phenotype of this disease beyond systemic-onset juvenile idiopathic arthritis

We identified a consanguineous Moroccan family with three affected siblings diagnosed with rheumatoid factor-negative polyarticular juvenile idiopathic arthritis. They all suffered from an early-onset (2-4 years-old) chronic and symmetric polyarthritis affecting both large and small joints. The joint involvement was markedly erosive in two siblings, with the older sister requiring hip prosthetic replacement at the age of 18 years. None of the patients had fever, skin rash, uveitis or other extra-articular manifestations. Laboratory analyses revealed leukocytosis, thrombocytosis, severe anaemia, marked increase of inflammatory markers and negative results for rheumatoid factor, anti-nuclear antibodies and HLA-B27.

Newly recognized Mendelian disorders with rheumatic manifestations.

We review newly discovered monogenic immune-dysregulatory disorders that were reported in Pubmed over the last year. Fourteen novel monogenic immune-dysregulatory disorders that present with innate and acquired/adaptive immune dysregulation and inflammatory clinical phenotypes were identified. These include autosomal-dominant gain-of function mutations in viral innate immune sensors or their adaptors, TMEM173/STING IFIH1/MDA5 and DDX58/RIG-I that cause complex clinical syndromes distinct from IL-1-mediated diseases and present with a chronic type I interferon (IFN Type I) signature in peripheral blood. Gain-of-function mutations in NLRC4 add a novel inflammasome disorder associated with predisposition to macrophage-activation syndrome and highly elevated IL-18 levels. Mutations in ADA2, TRNT1 and COPA, AP1S3, and TNFRSF11A cause complex syndromes; loss-of-function mutations in enzymes and molecules are linked to the generation of 'cellular stress' and the release of inflammatory mediators that likely cause the inflammatory disease manifestations. A monogenic form of systemic-onset juvenile idiopathic arthritis is caused by homozygous mutations in LACC1. Lastly, mutations in PRKDC (recessive), STAT3, CTLA4, and PIK3R1 (all dominant) lead to impaired central and peripheral T-cell tolerance and present with variable disease manifestations of immunodeficiency and immune dysregulation/autoimmunity. A number of novel monogenic diseases that present with innate and/or acquired immune dysregulation reveal novel immune pathways that cause human inflammatory diseases and suggest potential novel targets for treatment.

Macrophage activation syndrome, an important differential diagnosis for septic shock.

Macrophage activation syndrome (MAS) is a rare and life threatening complication of rheumatic diseases. It is seen most frequently in association with systemic onset juvenile idiopathic arthritis and less commonly in other rheumatic diseases of childhood including systemic lupus erythematosus. Recognition of MAS in patients with rheumatic diseases is often challenging as it may mimic the clinical features of the underlying disease. Sometimes MAS can be the mode of initial presentation adding to the diagnostic complexity. We describe two cases of MAS in association with systemic onset juvenile idiopathic arthritis who presented with a clinical picture suggestive of septic shock. The Internal Review Board at Shands Children's Hospital and the University of Florida waived the need for approval for these case reports.

Successful treatment of macrophage activation syndrome due to systemic onset juvenile idiopathic arthritis with antithymocyte globulin

Successful treatment of macrophage activation syndrome due to systemic onset juvenile idiopathic arthritis with antithymocyte globulin

From bench to bedside and back again: translational research in autoinflammation.

Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists.

Abstract 45: Incomplete Kawasaki Disease followed by Systemic Onset Juvenile Idiopathic Arthritis

Incomplete Kawasaki disease (KD) is second most common systemic vasculitis presented with persistent fever in childhood. Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare rheumatic arthritis characterized with spiking fever for more than 6 weeks with prominent painful joint swelling. KD may trigger or prodrome of SoJIA. Both diseases have overlapping clinical features and laboratory findings including fever, rash, lymphadenitis, thrombocytosis, arthralgia and coronary artery dilatation so that they could hardly be distinguished. We present 4 years old girl and 30 months old girl who presented with persistent fever, rash and arthralgia. They were initially diagnosed with incomplete KD and treated with intravenous immunoglobulin and steroids. Spiking fever and painful swelling of bilateral knee joints were noticed after 25days and 40days of illness. They were diagnosed with SoJIA followed by incomplete KD and treated with NSAIDs and MTX in addition. Neither coronary complication nor joint complication was noticed. Careful follow up is needed for patients with KD and arthralgia.

Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression of targeted mRNAs, which are important in the pathogenesis of autoimmune diseases. MiRNAs may have the potential to serve as biomarkers of disease. We evaluated serum levels of selected miRNAs and their associations with disease activity in juvenile idiopathic arthritis (JIA). Sera and peripheral blood leukocytes were collected from patients with JIA (8 systemic onset, 16 polyarthritis) and healthy controls. Levels of miR-16, miR-132, miR-146a, miR-155, and miR-223 were quantified. Levels of miR-223 in sera were significantly higher in patients in the active phase of systemic onset JIA than in controls. MiRNAs of peripheral blood leukocytes did not exhibit any difference between patients with JIA and controls. In both systemic onset JIA and polyarthritis patients, levels of miR-223 and miR-16 correlated with erythrocyte sedimentation rate and matrix metalloproteinase-3, respectively. MiR-146a and miR-223 in polyarthritis showed correlations with matrix metalloproteinase-3. Expressions of miRNAs were altered in patients with JIA. Serum levels of miR-223 may be a potential disease biomarker. Investigation of miRNAs could be helpful in understanding the pathogenesis of JIA and could aid in the identification of additional disease biomarkers.

Diagnosis of Systemic-Onset Juvenile Idiopathic Arthritis after Treatment for Presumed Kawasaki Disease

To estimate the incidence of systemic-onset juvenile idiopathic arthritis (SoJIA) within 6 months after treatment for presumed Kawasaki disease (KD) (presumed patients with KD with subsequent diagnosis of SoJIA [pKD/SoJIA]) and describe presentation differences from sole KD. We identified patients treated for KD at Nationwide Children's Hospital and from the Pediatric Health Information System from 2009-2013. We then identified the subset of children, pKD/SoJIA, who received an International Classification of Diseases, Ninth Revision code for SoJIA and had it listed at least once 3 months after and within 6 months after KD diagnosis. Demographic characteristics, readmission rates, treatments, and complications were noted. A literature review was also performed to identify clinical, laboratory, and echocardiographic data of previously documented patients with KD later diagnosed with SoJIA. There were 6745 total treated patients with KD in the Pediatric Health Information System database during the study period; 10 patients were identified to have pKD/SoJIA (0.2% of cohort). Those with pKD/SoJIA were predominantly Caucasian compared with patients with KD (90% and 46.8%, respectively; P=.003). Macrophage activation syndrome was more common in patients with pKD/SoJIA than in sole patients with KD (30% and 0.30%, respectively; P<.001). Fifteen cases of pKD/SoJIA were identified by literature and chart review, 12 of whom were initially diagnosed with incomplete KD. We reported a 0.2% incidence of pKD/SoJIA, which was associated with Caucasian race, macrophage activation syndrome, and an incomplete KD phenotype.