Oligoarticular Juvenile Idiopathic Arthritis Patients Research Articles

Factors determining resistance to conventional disease-modifying anti-rheumatic drug treatment in oligoarticular juvenile idiopathic arthritis.

Our study was designed to investigate the reasons for starting the conventional disease-modifying anti-rheumatic drugs (DMARDs) and the variables that impact the response to DMARD treatment in oligoarticular juvenile idiopathic arthritis (JIA) patients. Oligoarticular JIA patients (n = 187) were categorized into two groups: Group A consisted of patients who achieved remission with DMARD, and Group B comprised those who did not respond to DMARD therapy. DMARDs were initiated for various reasons: 68 (36.4%) due to active disease despite nonsteroidal anti-inflammatory drugs (± intra-articular corticosteroid) treatment, 59 (31.6%) due to uveitis, 49 (26.2%) due to extended oligoarticular JIA, and 11 (5.9%) due to inflammatory bowel disease. One hundred twenty-three patients (65.8%) achieved remission with DMARDs (Group A), while 64 patients (34.2%) did not respond to DMARD therapy (Group B). In Group B, patients had higher C-reactive protein (CRP) levels as well as higher Juvenile Idiopathic Arthritis Disease Activity Scores-71 (JADAS-71) at diagnosis (both p < 0.001). Moreover, extended oligoarticular JIA subtype (p = 0.017) and involvement of small joints at diagnosis (p = 0.043) were more prevalent among these patients. Group A exhibited a higher frequency of antinuclear antibody positivity (p = 0.014). Elevated CRP levels (> 1.1mg/dL) (OR 1.308, 95% CI 1.203-3.574; p < 0.001) and high JADAS-71 at diagnosis (> 15.8) (OR 1.659, 95% CI 1.179-2.941; p < 0.001) were associated with DMARD resistance. Elevated CRP and high JADAS-71 at diagnosis were the main factors associated with DMARD resistance in oligoarticular JIA. Prospective long-term studies may help verify the role of these factors associated with DMARD resistance in oligoarticular JIA. Key Points • Conventional DMARDs were most commonly started due to active disease despite NSAID (± intra-articular corticosteroids). • Remission was achieved with DMARD in 65.8% of oligoarticular JIA patients. • Elevated CRP and high JADAS-71 at diagnosis were associated with DMARD resistance.

When should the use of biological agents be considered in persistent oligoarticular juvenile idiopathic arthritis patients?

JADAS10 indicating ongoing severe disease activity at 3rd and 6th months rather than baseline JADAS10 is associated with the addition of bDMARDs. • Oligoarticular JIA patients have the best outcomes among JIA categories and respond favorably to first-line therapies such as non-steroidal anti-inflammatory drugs and intraarticular corticosteroid injections. • Clinically inactive disease rates have increased with the widespread use of biological agents in oligoarticular JIA patients who have not responded to initial therapies. • Approximately one-fifth of patients with persistent oligoarticular JIA on methotrexate may require the addition of a biological disease modifying anti-rheumatic drug during follow-up. • The JADAS10 calculated at 3 and 6months is a valuable tool to identify patients who should be added biological disease modifying anti-rheumatic drugs in persistent oligoarticular JIA.

Assessment of quality of life and physical activity in patients with oligoarticular juvenile idiopathic arthritis in remission.

The purpose of this study was to evaluate physical activity (PA) and health-related quality of life (HRQOL) in children with oligoarticular juvenile idiopathic arthritis (JIA) in remission in comparison with healthy peers and to determine the disease-related factors affecting PA levels. This study was conducted with 50 oligoarticular JIA patients in remission and 50 healthy peers between 9 and 14years. Demographic and clinical characteristics, laboratory parameters, and treatments were noted from electronic medical records. HRQOL was assessed with the Pediatric Quality of Life Inventory (PedsQL). PA was evaluated with the Physical Activity Questionnaire for Children (PAQ-C). Oligoarticular JIA patients had significantly lower self-reported median PedsQL scores in the domains of school functioning and social functioning compared to the control group (67.5 (10) vs. 75 (25), p = 0.001 and 70 (15) vs. 85 (26.3), p < 0.001, respectively). The median PAQ-C score was 2.6 (1.1) in patients with JIA and 3 (0.9) in their healthy peers (p = 0.02). The PAQ-C score was 2.8 (1.2) in patients < 8years at the disease onset and 2.3 (1) in those aged ≥ 8years (p = 0.022). There was no significant difference in the number of affected joints, type of affected joint, MTX and biologic agent treatment, and remission with or without drugs with the total score of the PedsQL and PAQ-C. All PedsQL domains were positively correlated with the PAQ-C. Conclusion: Oligoarticular JIA patients demonstrated lower PA and HRQOL scores compared to healthy controls despite favorable disease control. What is Known: • Oligoarticular JIA has fewer functional limitations and disabilities compared to other JIA subtypes. • As JIA can affect all aspects of a child's life, there is a need to improve the quality of life related to the disease. What is New: • It should be considered that patients with oligoarticular JIA may show lower PA and HRQOL scores compared to healthy controls despite favorable disease control. • Since there may be a relationship between PA and HRQOL, factors that may affect PA should be investigated to provide a holistic approach to JIA treatment.

Comparison of Biopsychosocial Characteristics of Children with Juvenile Idiopathic Arthritis According to Common Disease Subtypes.

In this study, we assessed the functional and biopsychosocial characteristics of juvenile idiopathic arthritis (JIA) patients according to disease subtypes. Child Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Disease Activity Score-71 (JADAS-71), and Juvenile Arthritis Biopsychosocial Questionnaire (JAB-Q) scales were administered to 304 JIA patients, and the subscale of JAB-Q was administered to their families. The median age of JIA patients at diagnosis was 7.9 (5.5-13) years (female/male = 1.3). Most patients were under treatment (68.7%) and had inactive disease (69.3%). While there was no significant difference between JADAS-71 scores according to the JIA subtypes, total CHAQ scores in polyarticular JIA patients were higher than in systemic JIA patients (P = .005). Enthesitis-related arthritis (ERA) patients had higher JAB-Q fatigue total scores compared to systemic JJIA patients (P = .001). Juvenile Arthritis Biopsychosocial Questionnaire-child psychosocial status scores were higher in polyarticular JIA patients than oligoarticular and systemic JIA patients (P = .004 and P = .003, respectively), and they had higher JAB-Q child form total scores than systemic JIA patients (P = .006). In addition, systemic JIA patients' parents had higher JAB-Q family total scores compared to oligoarticular JIA patients' parents (P = .03). Our results suggest that polyarticular JIA patients had higher CHAQ, JAB-Q psychosocial status, and child form total scores, and the JAB-Q fatigue score was higher in ERA patients. Also, JAB-Q-parent scores were higher in systemic JIA patients' parents. Biopsychosocial characteristics should be evaluated in both JIA patients and their parents.

Serum immunoglobulin A (IgA) levels in children affected with Juvenile Idiopathic Arthritis

Background and objectiveImmunoglobulin A (IgA) is the most abundant antibody isotype in the human body, considering its presence on the mucosal surfaces, in addition to the amount circulating in the bloodstream. Serum IgA levels can be variably altered in several pathological settings. However, very few studies specifically investigated serum IgA in Juvenile Idiopathic Arthritis (JIA). In the present study, we specifically assessed serum IgA levels in our cohort of patients affected with JIA. MethodsIn this cross-sectional study, serum IgA levels were measured in patients with JIA (and age-matched controls) and analyzed according to age class. The correlation of serum IgA levels with hematological, inflammatory, and disease activity parameters was assessed. ResultsNo significant difference in the frequency of low IgA levels (according to the definition of complete and partial IgA deficiency) was observed between JIA patients and controls, overall. This pediatric study population showed a progressive increase of total serum IgA concentrations with age, as expected; however, in JIA patients aged 10–17 years, total IgA serum levels resulted to be significantly higher than in age-matched control subjects. No clear correlation between IgA levels and the examined inflammatory, hematological, and disease activity parameters was observed in JIA patients, except for the erythrocyte sedimentation rate (ESR) in oligoarticular JIA patients: here, serum IgA levels showed a positive and moderate covariation with ESR, which was also observed for disease activity (JADAS-10) in selected oJIA patients without biological therapy. ConclusionsIn our cohort of JIA patients, total serum IgA levels were not reduced and were actually increased in adolescents compared to controls. Larger studies are needed to confirm this finding, which cannot be certainly explained based on the available data in this study, even though JIA disease control and/or chronic inflammation may be implicated to some extent.

Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers.

New early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients. Fourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples. We first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups. These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.

Identification of novel autoantigens as potential biomarkers in juvenile idiopathic arthritis associated uveitis.

Many children with juvenile idiopathic arthritis (JIA) have autoantibodies, targeting nuclear components (anti-nuclear antibodies, ANA). ANA in JIA is associated with uveitis, an eye inflammation which may cause permanent vision impairment if not detected and treated. However, ANA-testing is neither specific nor sensitive enough to be a clinically reliable predictor of uveitis risk, and the precise autoantigens targeted by ANA in JIA are largely unknown. If identified, specific autoantibodies highly associated with uveitis could be used as biomarkers to facilitate identification of JIA patients at risk. Antibodies from six ANA-positive, oligoarticular JIA patients, with and without uveitis, were explored by two large-scale methods: (1) screening against 42,100 peptides on an autoimmunity profiling planar array, and (2) immunoprecipitations from cell lysates with antigen identification by mass spectrometry. Three hundred thirty-five peptide antigens, selected from proteins identified in the large-scale methods and the scientific literature were investigated using a bead-based array in a cohort of 56 patients with oligoarticular- or RF-negative polyarticular JIA, eight of which were having current or previous uveitis. In the planar array, reactivity was detected against 332 peptide antigens. The immunoprecipitations identified reactivity towards 131 proteins. Only two proteins were identified by both methods. In the bead-based array of selected peptide antigens, patients with uveitis had a generally higher autoreactivity, seen as higher median fluorescence intensity (MFI) across all antigens, compared to patients without uveitis. Reactivity towards 17 specific antigens was significantly higher in patients with uveitis compared to patients without uveitis. Hierarchical clustering revealed that patients with uveitis clustered together. This study investigated autoantigens in JIA and uveitis, by combining two exploratory methods and confirmation in a targeted array. JIA patients with current or a history of uveitis had significantly higher reactivity towards 17 autoantigens and a generally higher autoreactivity compared to JIA patients without uveitis. Hierarchical clustering suggests that a combination of certain autoantibodies, rather than reactivity towards one specific antigen, is associated with uveitis. Our analysis of autoantibodies associated with uveitis in JIA could be a starting point for identification of prognostic biomarkers useful in JIA clinical care.

Neutrophils Lose the Capacity to Suppress T Cell Proliferation Upon Migration Towards Inflamed Joints in Juvenile Idiopathic Arthritis.

Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4+ T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4+ T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.

P010 Clinico-epidemiological characteristics and outcomes of Juvenile Idiopathic Arthritis (JIA) patients in Kenya: data from the KAPRI registry

Abstract Background Pediatric rheumatic diseases pose a significant disease burden upon children and their families (1–3). They lead to physical disability and diminished quality of life (1–3). Determination of the burden and clinical characteristics of these diseases is a critical first step to improving access to care and optimizing use of existing health systems for the well-being of these patients (4). This is in line with the goal of the Bone and Joint decade (2000–2010) aimed at increasing recognition and understanding of the impact of musculoskeletal diseases (5,6). The Kenya Pediatric Rheumatology Registry (KAPRI) offers a unique opportunity to pioneer and spearhead a systematic and organized format to inform policy and better healthcare provision. Our objective was to determine the patient characteristics, clinical features and outcomes of Juvenile Idiopathic Arthritis (JIA) patients assessed at the Aga Khan University Medical College East Africa from March 2019 to December 2020. Methods Data of JIA patients on age, gender, laboratory and clinical features at diagnosis and treatment options offered were extracted from the database. A further detailed chart review was undertaken to determine the proportion of patients who achieved remission or minimally active diseases. Results Among the 207 patients enrolled thus far, 16 (7.7%) were diagnosed to have JIA. Majority of the patients were females (75%; n = 12) with a mean age of 7 years and 3 months (Range : 1 year—13 years 7 months). All patients had joint pain and swelling as the initial presenting complaints. Majority of the patients had polyarticular JIA (75%, n = 12). The other 4 patients were oligoarticular (n = 2) and systemic JIA (n = 2). Among the polyarticular JIA patients (n = 12), only 3 (25%) were rheumatoid factor (RF) positive and 1 was antinuclear antibody (ANA) positive. The oligoarticular and systemic JIA patients were all negative for antinuclear antibody, rheumatoid factor and cyclic citrullinated peptide antibodies (anti-ccp). Seven patients (43.8%) required biological therapies; tocilizumab (n = 2: systemic JIA), adalimumab (n = 2: polyarticular JIA), etanercept (n = 2: polyarticular JIA) andtofacitnib (n = 1: polyarticular JIA). One patient with systemic JIA on tocilizumab developed herpes simplex which was successfully managed with oral acyclovir. All the other patients did not develop any infections, allergic reactions or any other untoward events as adverse outcomes following the use of biological therapies. Five patients have attained remission as illustrated in the table below. Two patients have been lost to follow up. Conclusion Seronegative polyarticular JIA was the predominant form of JIA observed with a predilection to affect more girls and boys. Over a period of 2 years, remission has been attained among 31.25% of the patients (5 of 16) with use of synthetic disease modifying anti-rheumatic drugs and biological therapies.

Patterns of etanercept use in juvenile idiopathic arthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry

BackgroundWe aimed to characterize etanercept (ETN) use in juvenile idiopathic arthritis (JIA) patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.MethodsThe CARRA Registry is a convenience cohort of patients with paediatric onset rheumatic diseases, including JIA. JIA patients treated with ETN for whom the month and year of ETN initiation were available were included. Patterns of ETN and methotrexate (MTX) use were categorized as follows: combination therapy (ETN and MTX started concurrently), step-up therapy (MTX started first and ETN added later), switchers (MTX started and then stopped when or before ETN started), MTX add-on (ETN started first and MTX added later), and ETN only (no MTX use). Data were described using parametric and non-parametric statistics as appropriate.ResultsTwo thousand thirty-two of the five thousand six hundred forty-one patients with JIA met inclusion criteria (74% female, median age at diagnosis 6.0 years [interquartile range 2.0, 11.0]. Most patients (66.9%) were treated with a non-biologic disease modifying anti-rheumatic drug (DMARD), primarily MTX, prior to ETN. There was significant variability in patterns of MTX use prior to starting ETN. Step-up therapy was the most common approach. Only 34.0% of persistent oligoarticular JIA patients continued treatment with a non-biologic DMARD 3 months or more after ETN initiation. ETN persistence overall was 66.3, 49.4, and 37.3% at 24, 36 and 48 months respectively. ETN persistence among spondyloarthritis patients (enthesitis related arthritis and psoriatic JIA) varied by MTX initiation pattern, with higher ETN persistence rates in those who initiated combination therapy (68.9%) and switchers/ETN only (73.3%) patients compared to step-up (65.4%) and MTX add-on (51.1%) therapy.ConclusionThis study characterizes contemporary patterns of ETN use in the CARRA Registry. Treatment was largely in keeping with American College of Rheumatology guidelines.

Prediction of inactive disease and relapse in oligoarticular juvenile idiopathic arthritis

Objective The aim of this study is to describe clinical features of patients with oligoarticular juvenile idiopathic arthritis (JIA) who achieved inactive disease at 3rd month and also to determine the predictors of relapse and extended course. Methods In the cohort study, 88 patients with oligoarticular JIA were retrospectively analyzed. The demographic data, clinical features, medications, relapse rates were recorded. Juvenile Arthritis Disease Activity Score (JADAS) and American College of Rheumatology Pediatric criteria were used to measure disease activity and treatment response at 3, 6 and 12 months. Results Fifty-nine (67%) patients were females and the mean age at diagnosis was 7.9 ± 4.3 years. The odds of achieving inactive disease (JADAS ≤1) at 3rd month were increased by a lower JADAS27 score at admission. Forty-one (48.8%) of 84 patients relapsed. Ankle involvement at onset, high JADAS27 score at admission, increased ESR at admission and presence of synovial hypertrophy in imaging were risk factors for occurrence of relapse. Conclusion Our results show that a significant proportion of oligoarticular JIA patients relapse after inactive period. JADAS is a useful tool to guide the treatment decisions of patients who may be at risk of high disease activity and relapse.

Update on the treatment of nonsystemic juvenile idiopathic arthritis including treatment-to-target: is (drug-free) inactive disease already possible?

This review concerns the outcome for nonsystemic juvenile idiopathic arthritis (JIA) with emphasis on treatment-to-target (T2T) and treatment strategies aiming at inactive disease by giving an overview of recent articles. More efficacious therapies and treatment strategies/T2T with inactive disease as target, have improved the outcome for JIA significantly. Recent studies regarding treatment strategies have shown 47-68% inactive disease after 1 year. Moreover, probability of attaining inactive disease at least once in the first year seems even higher in recent cohort-studies, reaching 80%, although these studies included relatively high numbers of oligoarticular JIA patients. However, 26-76% of patients flare upon therapy withdrawal and prediction of flares is still difficult. Remission can be achieved and sustained in (some) JIA patients, regardless of initial treatment. Cornerstone principles in the management of nonsystemic JIA treatment are early start of DMARD therapy, striving for inactive disease and T2T by close and repeated monitoring of disease activity. T2T and tight control appear to be more important than a specific drug in JIA. Next to inactive disease, it is important that patients/parents are involved in personal targets, like reduction of pain and fatigue. Future studies should focus on predictors (based on imaging-methods or biomarkers) for sustained drug-free remission and flare.

Evaluation of ocular surface and meibomian glands in patients with uveitis related to oligoarticular juvenile idiopathic arthritis.

To evaluate ocular surface changes and meibomian gland scores in patients with oligoarticular juvenile idiopathic arthritis. This prospective study was conducted at Ege University School of Medicine, Department of Ophthalmology. A total of 34 eyes of 17 patients with oligoarticular juvenile idiopathic arthritis and 30 right eyes of 30 age and gender-matched healthy subjects were included. Besides ophthalmic examination Schirmer 1 test, tear film break up time, Oxford staining scale and meibography were performed. There was no statistically significant differences between groups in terms of age, mean intraocular pressure, mean Schirmer 1 test value, tear film break up time and Oxford staining score. The median upper and lower eyelid meiboscore were 1 ± 0.60 (IQR = 1), and 0 ± 0.34 (IQR = 0) in Group 1, and they were 1 ± 0.56 (IQR = 0), 1 ± 0.12 (IQR = 1) in Group 2. Also, mean upper and lower meiboscores were statistically similar (p values 0.068 and 0.545, respectively). However, the median total meiboscore was 1 ± 0.42 (IQR = 1) in Group 1 and 1 ± 0.66 (IQR = 1) in Group 2. The difference was statistically significant (p = 0.041). Aqueous-deficient dry eye is a well-known condition in patients with rheumatologic diseases. However, evaporative dry eye and meibomian glands were not studied earlier. The current study demonstrated that total meiboscores of oligoarticular juvenile idiopathic arthritis patients are higher than normal subjects, which indicates a possible evaporative dry eye tendency in this entity.

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.

The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis.

OBJECTIVE:Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. Biologics have changed the faith of children with rheumatic diseases. The main objective of this study was to demonstrate the rate of usage, efficacy and safety of biologics in JIA subtypes.METHODS:This retrospective observational cohort study was conducted between May 2010 and September 2017. All children with the diagnosis of JIA and children under a biological agent treatment were recorded into the local registry system. Age, gender, JIA subtype, medications used, the clinical status of the patient, tuberculosis screening results, and side effects observed under biologics were retrieved from the registry.RESULTS:There were 405 patients with the diagnosis of JIA in the cohort. Biologics were used in 123 (30.3%) JIA patients. Subtype frequencies of JIA patients were as follows: persistent oligoarticular JIA (33.6%), enthesitis-related arthritis (29.2%), systemic JIA (13%), rheumatoid factor (RF)-negative polyarticular JIA (13%), extended oligoarticular JIA (4.2%), RF-positive polyarticular JIA (3.4%), psoriatic arthritis (1.8%) and unclassified arthritis (1.8%). The rate of biologic use was high in extended oligoarticular JIA (64.7% of the cases), RF-positive polyarticular JIA (57.1%), psoriatic arthritis (57.1%), RF-negative polyarticular JIA (41.5%), and in systemic JIA (39.6%). Enthesitis-related arthritis (27.1%), persistent oligoarticular JIA (17.6%) and unclassified arthritis (16.6%) patients were the cases that needed a biologic agent in the last order. At the last control, 78.9% of the cases were in remission, while 21.1% of them were active despite biologic treatment. Isoniazid prophylaxis was used in 30.8% of the patients. None of the patients developed active tuberculosis infection under prophylaxis. Adverse events were observed in 18.6% of patients under biologics as recurrent uncomplicated upper respiratory tract infections being the most common.CONCLUSION:Biologics are safe and effective treatment options in children with JIA. Most of the JIA patients with polyarticular involvement require biologics earlier in the disease course. The risk of tuberculosis infection seems not to be increased after appropriate screening and prophylaxis.

The transcription factor CREM drives an inflammatory phenotype of T cells in oligoarticular juvenile idiopathic arthritis

BackgroundInflammatory effector T cells trigger inflammation despite increased numbers of Treg cells in the synovial joint of patients suffering from juvenile idiopathic arthritis (JIA). The cAMP response element (CREM)α is known to play a major role in regulation of T cells in SLE, colitis, and EAE. However, its role in regulation of effector T cells within the inflammatory joint is unknown.MethodsCREM expression was analyzed in synovial fluid cells from oligoarticular JIA patients by flow cytometry. Peripheral blood mononuclear cells were incubated with synovial fluid and analyzed in the presence and absence of CREM using siRNA experiments for T cell phenotypes. To validate the role of CREM in vivo, ovalbumin-induced T cell dependent arthritis experiments were performed.ResultsCREM is highly expressed in synovial fluid T cells and its expression can be induced by treating healthy control PBMCs with synovial fluid. Specifically, CREM is more abundant in CD161+ subsets, than CD161− subsets, of T cells and contributes to cytokine expression by these cells. Finally, development of ovalbumin-induced experimental arthritis is ameliorated in mice with adoptively transferred CREM−/− T cells.ConclusionIn conclusion, our study reveals that beyond its role in SLE T cells CREM also drives an inflammatory phenotype of T cells in JIA.

Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways

Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression, and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T-cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease. Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T-cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T-cell activation markers (including HLA-DR) but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T-cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes epigenetic discrimination between clinical activity states, and reveals T-cell-related biological functions tied to, and possibly predicting or causing, clinical outcome.

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.

Clinical, Laboratory and Radiological Predictors of Extension of Oligoarticular Juvenile Idiopathic Arthritis: A Prospective Study

Background: Juvenile rheumatoid arthritis (JRA) is the most common chronic rheumatic illness in children and is a significant cause of both short- and long-term disabilities. The aim of this study is to detect clinical, laboratory and radiological predictors of oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype. Methods : This study included 40 oligoarticular JIA patients with no more than two years disease duration. Patients were divided into 2 groups after 6 months of illness into persistent and extended phenotypes. All patients were subjected to clinical, laboratory and conventional radiological assessment. Results : In extended JIA patients there was a significant increase in age of patients, upper limb joint involvement, bilateral symmetrical arthritis, disease activity and functional outcome measures. Moreover, a significant elevation of ESR and CRP levels and RF positivity, as well as ANA negativity and radiological findings of joint inflammation were evident in extended phenotype. Conclusion : Many clinical, laboratory and radiological predictors of conversion to extended oligoarticular JIA patients were close to charactertics of polyarticular form of the disease. doi:10.4021/ijcp29w

Ultrasonographic Measurement of the Femoral Cartilage Thickness in Patients with Juvenile Idiopathic Arthritis

Objective: To evaluate the femoral cartilage thicknesses of oligoarticular JIA patients (affected vs unaffected) by using ultrasonography (US), and to find out whether those US measurements were related with the clinical parameters of the patients. Methods: Twenty-six children (12 boys, 14 girls) with mono-articular (knee involvement) juvenile idiopathic arthritis ( JIA), with a mean age of 8.84±4.06 years were enrolled. Demographic and clinical features of the subjects including age, sex, body mass index, disease duration, age at onset, medical treatment, laboratory evaluations and presence of uveitis were all noted. The femoral cartilage thicknesses of both knees were measured with a 7-12 MHz linear probe while subjects’ knees were held in maximum flexion. Three mid-point measurements were taken from both knees (lateral condyle, intercondylar area and medial condyle) and the values relating to the unaffected knees were taken as controls. Results: Femoral cartilage thickness values were found to be similar (affected vs. non-affected sides) for all the three measurement sites (p values >0.05) and cartilage thickness values did not correlate with the clinical features of the patients.