Active Juvenile Idiopathic Arthritis Research Articles

P098 Anti-adalimumab antibodies are associated with active Juvenile Idiopathic Arthritis

Abstract Background/Aims Biologics have been used widely in the UK to treat Juvenile Idiopathic Arthritis (JIA) for over two decades. As this population has aged and switched biologics, there has been a growth in the cohort of patients who have switched through a greater number of biologics, consequently having fewer therapeutic options available. Our group has recently published data suggesting adalimumab has a greater drug survival compared to etanercept and infliximab. As part of our further investigation, we examined the relationship between adalimumab antibodies (AAA) and drug levels, stratified by disease activity (remission vs. active disease). Methods We conducted a retrospective observational study among patients with JIA and measured adalimumab drug levels and AAAs. The key metrics measured were AAAs (AU/L) and adalimumab drug levels (mg/mL). Disease remission was determined using standard Wallace criteria.The differences between the active and remission groups were examined with the Mann-Whitney U test. Results Among our cohort of 293 JIA patients receiving adalimumab, 179 had recorded adalimumab levels and AAAs. In 146 of these patients, we were able to measure disease activity, which was stratified into two distinct categories: Remission (N = 96) and Active (N = 50) according to Wallace criteria. Within our cohort of patients, there was a significant difference in both adalimumab drug levels, (P = 0.004) and AAAs (P = 0.00009) among those with active disease when compared to those in remission. Specifically, those with active disease exhibited a higher geometric mean AAA of 156.89 AU/L [95% CIs (95% confidence intervals) 129.65-189.85] when compared to those in remission with a mean of 65.25 AU/L (95% CI 41.10-103.58). The median AAA levels in those with active disease was 91 AU/L (IQR 0-200), compared with 0 (IQR 0-12.5) among those in remission. With respect to adalimumab drug levels, the geometric mean in patients with active disease was 7.27 mg/mL (95% CI 5.15-10.26) compared with 8.55 mg/mL (95% CI 7.26, 10.07) for patients in remission. The median drug level in the active group was 2.3 mg/ml (IQR 0-11.9) when compared with 9.4 mg/ml (IQR 3.8-13.1) in the remission group. Conclusion Various studies have demonstrated that the presence of AAAs is associated with secondary failure in JIA and other rheumatic diseases. However, the precise relationship between AAAs, adalimumab drug concentration and disease activity are yet to be elucidated, thus their regular monitoring is not currently part of guidelines or routine clinical practice.To our knowledge this is the largest single-centered cross-sectional study investigating the relationship of AAAs and remission state in JIA.Our study demonstrates that not only are higher AAAs associated with lower drug concentration, but that this is further associated with active disease. Disclosure M.W. Carrim: None. D. Sen: None. M. Shipa: None. C. Fisher: None. T. AlSulaim: None. A. Bouraoui: None. M. Leandro: None. C. Ciurtin: None. J. Glanville: None.

RISK FACTORS AND CLINICAL CORRELATIONS OF URINARY TGF-Β1 IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS AND EARLY KIDNEY FIBROSIS

The course of juvenile idiopathic arthritis (JIA) is associated with a long-term infl ammatory process and the use of nonsteroidal anti-infl ammatory drugs (NSAIDs), which can cause nephrotoxicity with fi brotic kidney damage in patients with JIA. Regardless of the etiology of joint damage, prolonged infl ammation promotes the progression of fi brosis, and renal fi brosis is the fi nal common stage of chronic kidney disease (CKD). Kidney biopsy, which is invasive, risky and underutilized, is generally considered the only clinical method to detect fi brosis. Over the past decade, some progress has been made in the search for minimally invasive biomarkers of early kidney fi brosis, with transforming growth factor-β1 (TGF-β1) playing a key role in the progression of kidney fi brosis, but the signifi cance of TGF-β1 in children with JIA is unknown.Material and Methods: 80 children with JIA were examined. Urinary TGF-β1 levels were determined using a TGF-β1 ELISA kit(DRG International, Inc., Germany, EIA-1864) according to the manufacturer’s instructions. Methods of variation statistics were used. Informed consent was obtained from all patients. The study has a positive conclusion of the Commission on Biomedical Ethics of Dnipro State Medical University (Minutes of the meeting of the Commission No. 12 dated December 19, 2002), which decided that the scientifi c research can be considered in accordance with generally accepted moral standards, the requirements of respecting the rights, interests and personal dignity of study participants, bioethical standards for work with pediatric patients. There is no risk to the research subjects in the performance of the work. The legal representatives of the children involved in the research are informed about all aspects related to the purpose, objectives, methods and expected benefi ts of the research. Laboratory and instrumental research methods are generally accepted; the drugs to be used are approved for use. No human experiments were performed.Methods of variation statistics were used. Statistical analysis was performed using the STATISTICA 6.1 software package(StatSoft Inc., serial no. AGAR909E415822FA). The work was carried out as part of the research work of the Department of Propaedeutic of Childhood Diseases and Pediatrics 2 of the Dnipro State Medical University «Development of criteria for early diagnosis and prediction of comorbid kidney damage in children with somatic and infectious diseases» (state registration No. 0119U100932, implementation period 01.2019-12.2023).Results. The mean TGF-β1 level in our study was 20.26±16.34 (14.02, 12.5-17.98) pg/ml. Polyarthritis almost quadrupledthe probability of pathological changes in TGF-β1. The overwhelming majority of children with elevated TGF-β1 suff ered from polyarthritis (80.0 %) – one and a half times more often than those with relatively normal TGF-β1 concentration, p<0.04.If the active stage of the disease lasted at least 4 years, the probability of elevated TGF-β1 increased more than sixfold. Thetendency of signifi cant nephrotoxic eff ect of prolonged active JIA was confi rmed by the results of correlation analysis, according to which, in general, the duration of active JIA was directly related to the increase of TGF-β1 (ρ=0.38, p<0.001), and the duration of remission and the total duration of JIA had no signifi cant correlation with it (ρ= –0.19 and ρ=0.18, respectively, p>0.05). The direct dependence of elevated urinary TGF-β1 levels on clinical features such as polyarthritis and the duration of the active phase of JIA has been demonstrated. These clinical features in children with JIA can be considered as risk factors for the development of early renal fi brosis. Against the background of elevated TGF-β1, a reduced GFR according to the Hoek formula (<90 ml/min/1.73 m2) was found in 95 % of cases, i. e. the estimates of the functional state of the kidneys obtained by two diff erent methods were quite clearly the same. In the sample with TGF-β1<17.98 pg/ml, 22.76 % of children received immunobiologic therapy, while in the sample to increase TGF-β1 – only 14.76 %. Immunobiological therapy reduced the risk of increasing this urinary marker by 5.5 times.Conclusions. Elevated levels of the TGF-β1 biomarker were found in 25 % of children with JIA. An association of early renalfi brosis with duration of active phase of JIA ≥ 4 years, increased ESR, polyarthritis, arterial hypertension, and dental carieswas observed. Elevated urinary TGF-β1 levels are associated with reduced eGFR and are observed in almost all children witheGFR<90 ml/min/1.73 m2, confi rming the importance of early renal fi brosis in the development of renal dysfunction.

Preterm birth, preeclampsia, gestational hypertension and offspring birth weight in women with active juvenile idiopathic arthritis and healthy controls

ObjectivesThere is insufficient knowledge about pregnancy outcomes in women with juvenile idiopathic arthritis (JIA). Our objective was to explore a possible association of inflammatory active JIA and pregnancy outcomes, including preterm birth, preeclampsia, gestational hypertension, and offspring gestational weight.MethodsWe linked data from the Norwegian nationwide observational register RevNatus with data from the Medical Birth Registry of Norway (MBRN) for the period 2010 to 2019. Singleton births in women with JIA (n = 181) included in RevNatus were cases. After excluding births in mothers with rheumatic inflammatory diseases, the remaining singleton births registered in MBRN, served as population controls (n = 575 798).ResultsPreterm birth was more frequent in women with active JIA (17.6%) and of equivalent frequency in women with inactive JIA (3.1%), compared to population controls (4.9%). Preeclampsia had similar rates in women with JIA and population controls while gestational hypertension was more frequent in women with active JIA (7.2%) and inactive JIA (6.9%) compared to population controls (1.7%). Abnormal fetal growth occurred in similar rates in women with JIA and population controls.ConclusionHaving active JIA in pregnancy increased the risk for preterm birth (risk difference 12.7, 95% CI 4.7 to 25.3) and gestational hypertension (risk difference 6.2, 95% CI 1.4 to 16.8). There was no increased risk for preeclampsia or abnormal fetal growth compared to population controls.

Serum and salivary inflammatory biomarkers in juvenile idiopathic arthritis—an explorative cross-sectional study

BackgroundBiomarkers may be useful in monitoring disease activity in juvenile idiopathic arthritis (JIA). With new treatment options and treatment goals in JIA, there is an urgent need for more sensitive and responsive biomarkers.ObjectiveWe aimed to investigate the patterns of 92 inflammation-related biomarkers in serum and saliva in a group of Norwegian children and adolescents with JIA and controls and in active and inactive JIA. In addition, we explored whether treatment with tumor necrosis factor inhibitors (TNFi) affected the biomarker levels.MethodsThis explorative, cross-sectional study comprised a subset of children and adolescents with non-systemic JIA and matched controls from the Norwegian juvenile idiopathic arthritis study (NorJIA Study). The JIA group included individuals with clinically active or inactive JIA. Serum and unstimulated saliva were analyzed using a multiplex assay of 92 inflammation-related biomarkers. Welch’s t-test and Mann–Whitney U-test were used to analyze the differences in biomarker levels between JIA and controls and between active and inactive disease.ResultsWe included 42 participants with JIA and 30 controls, predominantly females, with a median age of 14 years. Of the 92 biomarkers, 87 were detected in serum, 73 in saliva, and 71 in both biofluids. A pronounced difference between serum and salivary biomarker patterns was found. Most biomarkers had higher levels in serum and lower levels in saliva in JIA versus controls, and in active versus inactive disease. In serum, TNF and S100A12 levels were notably higher in JIA and active disease. The TNF increase was less pronounced when excluding TNFi-treated individuals. In saliva, several biomarkers from the chemokine family were distinctly lower in the JIA group, and levels were even lower in active disease.ConclusionIn this explorative study, the serum and salivary biomarker patterns differed markedly, suggesting that saliva may not be a suitable substitute for serum when assessing systemic inflammation in JIA. Increased TNF levels in serum may not be a reliable biomarker for inflammatory activity in TNFi-treated children and adolescents with JIA. The lower levels of chemokines in saliva in JIA compared to controls and in active compared to inactive disease, warrant further investigation.

A Study on the Immunoregulatory Role of the PD1 Pathway in Juvenile Idiopathic Arthritis.

To investigate the immunoregulatory role of the Programmed-cell-Death-protein-1 (PD1) pathway, an inhibitory immune checkpoint, in Juvenile Idiopathic Arthritis (JIA). The PD1 expression on CD4+ and CD8+ T-cells was determined by flow cytometry and the PD1 soluble form (sPD1) levels by ELISA, in peripheral blood (PB)/serum and synovial fluid (SF) samples of JIA patients and healthy controls (HCs). We searched for any association in-between the biomarkers and with JIA activity. 101 Caucasian patients (69 female), aged 12 (8-15) years, and 20 HCs participated in this study. The PB PD1 expression on T-cells was higher in: a. JIA patients vs HCs (CD4: 1.24% vs 0.32%, p=0.007, CD8: 1.6% vs 0.4%, p=0.002). b. active vs inactive JIA (CD4: 1.44% vs 0.87%, p=0.072, CD8: 2.1% vs 0.93%, p=0.005). The SF PD1 expression on T-cells correlated strongly and positively with the disease activity (CD4: ρ=0.55, p=0.022, CD8: ρ=0.555, p=0.026). The SF PD1 expression on CD8 T-cells was higher in patients on-treatment vs those off-treatment (21.3% vs 5.83% p=0.004). The sPD1 levels were higher in the SF vs the serum (801pg/ml vs 367.2, p=0.013), without an association with disease activity. These results indicate an up-regulation of the PD1-pathway in JIA, at least quantitatively, especially in active disease. sPD1 is compartmentally produced at the inflamed joints. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unravelling the precise role of the PD1 pathway in the pathogenesis and persistence of the joint inflammation.

Validity of an ultrasonographic joint-specific scoring system in juvenile idiopathic arthritis: a cross-sectional study comparing ultrasound findings of synovitis with whole-body magnetic resonance imaging and clinical assessment

ObjectiveTo assess the validity of an ultrasonographic scoring system in juvenile idiopathic arthritis (JIA) by comparing ultrasound detected synovitis with whole-body MRI and clinical assessment of disease activity.MethodsIn a cross-sectional...

Macrophage IL-1β-positive microvesicles exhibit thrombo-inflammatory properties and are detectable in patients with active juvenile idiopathic arthritis.

IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions in vitro and in vivo. The second objective was to detect circulating IL-1β-positive MVs in JIA patients. MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied in vitro by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized. In vivo, MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1β-positive MVs were studied ex vivo in 10 active JIA patients using flow cytometry. THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation in vitro. In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1β-positive MVs were detectable in plasma from 10 active JIA patients. MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.

NKG2D receptor regulates CD4+T cell differentiation via interaction with dendritic cells in patients with juvenile idiopathic arthritis

NKG2D provides a costimulatory signal for activation of CD4+ T cells. We explored its role in interactions of CD4+ T cells and dendritic cells (DCs) in juvenile idiopathic arthritis (JIA) patients by using NKG2D genetically modified CD4+ T cells. We found active JIA patients had significantly higher content of CD4 + NKG2D+ T cells than healthy controls. Expression of NKG2D on CD4+ T cells, and MICA and MICB on DCs were significantly greater in articular JIA than systemic JIA. NKG2D induced IL- 12 and suppressed IL-10 and TGF-β from CD4+ T cells, increased IFN-γ + CD4+ T and IL-17+ CD4+ T cells, RORc and T-bet, but reduced CD25+ Foxp3+ CD4+ T cells, IL-4+ CD4+ T cells, Foxp3, and GATA3 in JIA patients. NKG2D decreased IL-10 and increased CD83, MICA, and MICB of DCs in JIA and controls. So NKG2D regulates differentiation of CD4+ T cells directly and the maturation of DCs indirectly.

Golimumab for Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis: Pharmacologic and Clinical Considerations.

Psoriatic arthritis is a chronic debilitating autoimmune condition, and when diagnosed in patients before the age of eighteen, it is considered pediatric polyarticular juvenile idiopathic arthritis. Monoarticular or polyarticular psoriatic arthritis can be distinguished from other arthropathies by its unique cutaneous manifestations. With numerous treatments already in clinical practice, there are numerous options for treatment. The current literature indicates an elevated level of tumor necrosis factor is present in the epidermis of patients with psoriatic arthritis when compared with the general population. For this reason, anti-tumor necrosis factor therapies have become a hallmark option for psoriatic arthritis patients. Golimumab, a human monoclonal antibody tumor necrosis factor-alpha (TNF-a) receptor antagonist, was chosen as the focus therapy for this investigation. The mechanism of action behind anti-tumor necrosis factor-alpha blockers involves the binding of human TNF-a soluble and transmembrane proteins to competitively inhibit TNF-a from binding to its cellular receptors. The present investigation evaluated current treatment options available for both juvenile- and adult-onset psoriatic arthritis and compared them with the efficacy seen with golimumab use. Pediatric patients included children ages 2-17, while adult populations included adults 18-83 years old. The Food and Drug Administration has approved golimumab for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis. The results of four different studies reporting on the therapeutic effects and adverse events of golimumab use in psoriatic arthritis, juvenile psoriatic arthritis, juvenile idiopathic arthritis, and juvenile polyarticular arthritis were used for comparison. The meta-analysis referenced studies including children ages 2-17 with no reference mentioning children less than age 2. Based on the results of each study, it can be concluded that golimumab, a human monoclonal antibody that prevents the activation of cellular inflammatory reactions when it binds to the TNF-a receptor, is an effective option for patients with active psoriatic arthritis and psoriatic juvenile idiopathic arthritis and for patients who are no longer responding to their current treatment with adalimumab. Each study also reported minimal adverse events associated with golimumab use, and the drug can be safely used in the pediatric population.

Knee acoustic emissions as a noninvasive biomarker of articular health in patients with juvenile idiopathic arthritis: a clinical validation in an extended study population

BackgroundJoint acoustic emissions from knees have been evaluated as a convenient, non-invasive digital biomarker of inflammatory knee involvement in a small cohort of children with Juvenile Idiopathic Arthritis (JIA). The objective of the present study was to validate this in a larger cohort.FindingsA total of 116 subjects (86 JIA and 30 healthy controls) participated in this study. Of the 86 subjects with JIA, 43 subjects had active knee involvement at the time of study. Joint acoustic emissions were bilaterally recorded, and corresponding signal features were used to train a machine learning algorithm (XGBoost) to classify JIA and healthy knees. All active JIA knees and 80% of the controls were used as training data set, while the remaining knees were used as testing data set. Leave-one-leg-out cross-validation was used for validation on the training data set. Validation on the training and testing set of the classifier resulted in an accuracy of 81.1% and 87.7% respectively. Sensitivity / specificity for the training and testing validation was 88.6% / 72.3% and 88.1% / 83.3%, respectively. The area under the curve of the receiver operating characteristic curve was 0.81 for the developed classifier. The distributions of the joint scores of the active and inactive knees were significantly different.ConclusionJoint acoustic emissions can serve as an inexpensive and easy-to-use digital biomarker to distinguish JIA from healthy controls. Utilizing serial joint acoustic emission recordings can potentially help monitor disease activity in JIA affected joints to enable timely changes in therapy.

HLA-DRB1*15 and Eosinophilia Are Common Among Patients With Systemic Juvenile Idiopathic Arthritis.

Concern exists that medications used to treat patients with systemic juvenile idiopathic arthritis (JIA), particularly interleukin (IL)-1 and IL-6 blocking agents, might be causing adverse drug reactions and lung disease (systemic JIA-LD). Carriage of HLA-DRB1*15 has been reported as a risk factor for adverse drug reactions among patients with systemic JIA. We performed a retrospective chart review to evaluate these factors at our center. We reviewed the records of 86 subjects with systemic JIA followed for at least 6 months between 1996 and 2022. HLA typing was performed in 23 of the subjects. We compared characteristics of patients with or without eosinophilia. Among patients with HLA typing, we compared clinical characteristics of subjects with or without DRB1*15 and with or without systemic JIA-LD. Among the 23 patients with HLA typing, 74% carried DRB1*15, and 63% of patients without systemic JIA-LD carried DRB1*15. Seven subjects had systemic JIA-LD, all of whom carried DRB1*15. Patients with systemic JIA-LD were younger at the time of diagnosis and more likely to have had macrophage activation syndrome. Exposure to IL-1 and IL-6 blockers was common, occurring in 95% of patients. Eosinophilia occurred in 39% of patients with systemic JIA, often before IL-1 or IL-6 blockade. Eosinophilia was associated with adverse drug reactions and macrophage activation syndrome. There was 1 death, unrelated to active systemic JIA disease. Carriage of DRB1*15 was more common in this cohort of patients with systemic JIA than in the general population. Eosinophilia and systemic JIA-LD were more common among patients with severe systemic JIA complicated by macrophage activation syndrome.

Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis

To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.

The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study.

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

Gait parameters, functional performance and physical activity in active and inactive Juvenile Idiopathic Arthritis

BackgroundChildren with Juvenile Idiopathic Arthritis (JIA) may adopt different movement patterns and participate in physical activity during different states of disease. Research questionWhich specific features of gait and physical function performance differ among children with active or inactive JIA compared to healthy children? MethodsForty-three children participated (14.5 ± 4.2 yrs; 60 % female). 3D-motion analysis methods were coupled with force measures from an instrumented treadmill captured gait mechanical measures. The 30-second Chair Rise Test (repetitions) and stair ascent-descent tests were performed, and the 11-point Wong-Baker face scale assessed pain after each test. ResultsCompared to healthy controls children with active and inactive JIA had worse outcomes (12–21 % slower self-selected and fast walking speeds, 28–34 % slower stair navigation times, 28 % fewer chair rise repetitions in 30 s; all p < .05). Children with active JIA had 8–13 % slower gait speeds, 4 % fewer chair rise repetitions and 14–16 % slower stair navigation times. At faster walking speed, children with active JIA had less hip joint flexion/extension excursion in the sagittal plane during the gait cycle, produced higher leg stiffness, and demonstrated greater interlimb asymmetry in GRF vertical impulse during loading than healthy children (all p < .05). The Pedi-FABS subscore of “Duration: performing athletic activity for as long as you would like without stopping” was rated lower in children with active JIA compared to controls (p < .05). ConclusionGait speed, specific load-bearing functional tasks and leg stiffness features of gait may be informative ‘functional biomarkers’ for assessing JIA burden and tracking treatment efficacy. Additional prospective studies are needed to determine how these features change over time with pain change, and understand impact on quality of life and physical activity participation.

Increased histone citrullination in juvenile idiopathic arthritis.

ObjectivePosttranslational modifications (PTMs) of proteins are crucial for regulating various biological processes. However, protein alteration via PTMs, and consequently, the creation of new epitopes, can induce abnormal autoimmune responses in predisposed individuals. Immunopathogenesis of several rheumatic diseases, including the most common childhood form, juvenile idiopathic arthritis (JIA), is associated with the generation of autoantibodies against such modified proteins. Dysregulated generation of neutrophil extracellular traps (NETs) can be a source of post-translationally altered proteins. Thus, we investigated the role of PTMs and the presence of NET-associated markers in JIA patients.MethodsWe recruited 30 pediatric patients with JIA (20 with active disease and 10 in remission) and 30 healthy donors. The serum concentrations of citrullinated histone H3 (citH3), peptidyl arginine deiminases (PADs), and NET-related products were detected using ELISA, and the number of citH3+ neutrophils was assessed using flow cytometry.ResultsThe serum levels of citH3 and PADs were higher in active as well as in remission JIA patients than in healthy donors. Similarly, the number of citH3+ neutrophils was higher in the peripheral blood of patients with JIA, implying an enhanced process of NETosis. This was effectively reflected by elevated serum levels of NET-associated products, such as neutrophil elastase, LL37, and cell-free DNA-histone complexes. Additionally, 16.7% of active JIA patients were seropositive for carbamylated autoantibodies, the levels of which declined sharply after initiation of anti-TNFα therapy.ConclusionCollectively, our data suggest that the accelerated process of NETosis and PTMs in JIA may result in the generation of anti-citrullinated/carbamylated autoantibodies against various epitopes later in life, which could be prevented by effectively regulating inflammation using immune therapy.

Evidence of persistent glial cell dysfunction in the anterior cingulate cortex of juvenile idiopathic arthritis children: a proton MRS study

BackgroundThis study aims to investigate whether the neurometabolites of the anterior cingulate cortex (ACC) were distinct in patients with active and inactive juvenile idiopathic arthritis (JIA) using the proton magnetic resonance spectroscopy.MethodsWe measured the levels of total N-acetylaspartate (tNAA), choline (Cho), myo-inositol (ml), glutamate (Glu) and the complex of glutamate and glutamine (Glx) relative to total creatine (tCr) in ACC of each participant.ResultsCompared with the healthy controls, a significant decrease of total Cho/tCr and Glx/tCr ratio in ACC occurred in active and inactive JIA group. The tCho/Cr level was negatively associated with the serum level of ESR in active JIA patients. There was no difference in NAA/tCr ratio among the three groups, which may imply that no neuron and axonal losses occurred in either active or inactive JIA patients.ConclusionsThe abnormal neurometabolites in tCho/tCr and Glx/tCr in ACC may indicate that persistent dysfunction of glial cell, while neither neuron nor axonal losses occurred in active and inactive JIA patients.

Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis.

Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD. We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated. Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD.

Increased risk of temporomandibular joint disorders and craniofacial deformities in patients with juvenile idiopathic arthritis: a population-based cohort study

Juvenile idiopathic arthritis (JIA) is an autoimmune disease that has been proposed to involve the temporomandibular joint (TMJ). The aim of this study was to identify the relationships between JIA, TMJ disorders, and craniofacial deformities. This cohort study included patients diagnosed with clinically active JIA between 1999 and 2013 through a nationwide longitudinal health registry. The primary outcome was the presence of a TMJ disorder. The secondary outcome was the presence of a JIA-associated craniofacial deformity. A total of 2791 patients with JIA were included in the case group; 11,164 propensity score-matched individuals without JIA were selected from the same database as controls. TMJ disorders were present in 142 individuals: 48 (1.72%) in the case group and 94 (0.84%) in the control group (relative risk 2.047, 95% confidence interval 1.446–2.898). Craniofacial deformities were present in 374 individuals: 112 (4.01%) in the case group and 262 (2.35%) in the control group (relative risk 1.722, 95% confidence interval 1.380–2.148). Patients with JIA showed a significantly greater likelihood of developing TMJ disorders and craniofacial deformities compared to matched controls.

Synovial signal intensity on static contrast-enhanced MRI for evaluation of disease activity in juvenile idiopathic arthritis – A look at the bright side of the knee

BackgroundKnowledge on the role of synovial signal intensity (SI) grading on static contrast-enhanced (CE) MRI of the knee for assessment of disease activity in juvenile idiopathic arthritis (JIA) is lacking. ObjectivesTo assess the value of synovial SI on static CE-MRI of the knee for evaluation of disease activity in children with JIA. Materials and methodsChildren with clinically inactive and clinically active JIA who underwent static CE-MRI of the knee were included. Synovial SI was evaluated on post-contrast T1-weighted fat-saturated images using a 0.02 cm2 region of interest drawn in the area of the synovium that contained visually the highest SI. To control for potential time-dependent post-contrast enhancement variability, a ratio between the SI of the synovium to the musculus gastrocnemius was calculated. ResultsWe included 427 JIA patients (clinically inactive JIA: 150 [35,1%]; clinically active JIA: 277 [64.9%]), 65.3% female, with a mean age of 13.3 ± 3.2 years. Mean SI synovium-to-muscle ratio was 2.1 ± 0.7 in patients with clinically inactive JIA versus 2.2 ± 0.8 in patients with clinically active JIA. Subgroup analysis showed no significant difference in SI synovium-to-muscle ratio between JIA patients with clinically inactive disease and JIA patients with clinically active disease (p-value 0.22). ConclusionsEvaluation of the brightness of the synovium on static CE-MRI of the knee for assessment of JIA disease activity should be avoided, as this might lead to incorrect clinical conclusions.

Discordance between Clinical and Ultrasound Examinations in Juvenile Idiopathic Arthritis: An Experimental Approach.

Clinical examination (CE) and musculoskeletal ultrasound (MSUS) of ten joints (knee, ankle, wrist, elbow, II-MCP) and their extra-articular (EA) compartments (tendons and bursae) were performed on 35 consecutive patients with active juvenile idiopathic arthritis (JIA) (active group) to test how the extension of MSUS examinations to EA changes the concordance between MSUS and CE. The overall concordance between CE and MSUS, measured with Cohen’s Kappa (k), was moderate (k = 0.43); the addition of EA MSUS increased the concordance in all joints, with the exclusion of II-MCP (k = 0.49). In the ankle and wrist, the k increase was relevant (k from 0.13 to 0.27 and 0.11 to 0.41). In the active group patients, we observed 44 subclinical synovitis; the number of subclinical synovitis per patient was correlated with JADAS-27 (p = 0.03) and was higher in a control group composed of 15 patients with persistent disease remission (1.3 vs. 0.4 p = 0.03). Our results show that EA compartments should always be evaluated during MSUS. Furthermore, we demonstrate a moderate concordance between CE and MSUS in JIA; the finding of subclinical synovitis is common in patients with active diseases and is related to disease activity.