Biomarkers For Juvenile Idiopathic Arthritis Research Articles

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.

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.

Rheumatoid factor value for determining the first biologic agent to use for non-systemic juvenile idiopathic arthritis.

Currently, no indicators on which biologic disease-modifying anti-rheumatic drugs (bDMARDs) should be used first for juvenile idiopathic arthritis (JIA) have been established. Thus, this study aimed to determine the useful biomarkers in JIA to enable the best selection of the first bDMARDs without primary failure. This retrospective study used data of patients examined for JIA between 2015 and 2021 at Kagoshima University Hospital in Japan. Altogether, 67 cases of non-systemic JIA were analyzed, excluding cases that had been treated for <6 months. Of the 67 cases, 52 were treated with bDMARDs and all rheumatoid factor (RF)+ types (32 cases) were treated with bDMARDs. Eleven cases (31.4&) (all were RF+ types and used anti-tumor necrosis factor (TNF)α agents) switched to other bDMARDs because of primary failure, and nine cases had secondary failure (6;anti-TNF, 3;anti-Interleukin-6). A significant difference in pre-treatment RF values (177.9 vs 25.7 IU/ml, p = 0.002) and presence (Odds Ratio 1.952,p = 0.004) were observed between the primary failure group and effective group. RF+ JIA required bDMARDs with high probability. JIA with high titre of RF tends to be refractory to anti-TNFα agents. Tocilizumab or abatacept could be a first-choice bDMARD in such cases.

Identification of molecular patterns and diagnostic biomarkers in juvenile idiopathic arthritis based on the gene expression of m6A regulators.

The role of N6-methyladenosine modification in immunity is increasingly being appreciated. However, the landscape of m6A regulators in juvenile idiopathic arthritis (JIA) is poorly understood. Thus, this study explored the impact of m6A modification and related lncRNAs in JIA immune microenvironment. Fourteen m6A regulators and eight lncRNAs were identified as potential diagnostic biomarkers for JIA. Two diagnostic models for JIA were also constructed. The putative molecular regulatory mechanism of FTO-mediated m6A modification in JIA was hypothesized. Three distinct m6A patterns mediated by 26 m6A regulators and three diverse lncRNA clusters mediated by 405 lncRNAs were thoroughly investigated. They exhibited dramatically diverse immune microenvironments and expression of HLA genes. The identification of two separate subtypes of enthesitis-related arthritis implies that our work may aid in the establishment of a more precise categorization system for JIA. m6A modification-related genes were obtained, and their underlying biological functions were explored. The m6Ascore system developed for individual JIA patients may be utilized to evaluate the immunological state or molecular pattern, thereby offering therapy recommendations. In short, through the investigation of the m6A regulators in JIA, the current work may contribute to our knowledge of the pathophysiology of JIA.

α2-fraction and haptoglobin as biomarkers for disease activity in oligo- and polyarticular juvenile idiopathic arthritis

ObjectivesUnlike in adult rheumatology, for most forms of juvenile idiopathic arthritis (JIA) no reliable biomarkers currently exist to assess joint and disease activity. However, electrophoresis is frequently found changed in active juvenile arthritis. The objective of this study was to evaluate the α2-fraction of serum electrophoresis and its main components as biomarkers for JIA, categories extended/persistent oligoarthritis and seronegative polyarthritis, in comparison with the conventionally used erythrocyte sedimentation rate and C-reactive protein.MethodsSerum samples and clinical data from 181 patients with JIA were collected. Serum electrophoresis and α2-fraction and its components were determined using standard methods. Relationship between calculated α2-fraction of serum electrophoresis (CA2F) and its components, acute-phase parameters and cJADAS27 was assessed using Pearson’s correlation coefficient and linear regression modelling, adjusting for confounding effects. Results were confirmed in a second cohort with 223 serum samples from 37 patients, using a mixed model to account for repeated measures.ResultsCompared to ESR and CRP, CA2F showed higher correlation to cJADAS27, in particular for persistent oligoarthritis. Of the three components of the α2-fraction, haptoglobin showed the highest correlation to cJADAS27. Regression analysis demonstrated higher ability to predict cJADAS27 for CA2F, and especially for haptoglobin as a component thereof, than for CRP and ESR.ConclusionCompared to conventional methods, α2-fraction of serum electrophoresis and specifically, haptoglobin show higher correlations with disease activity in common subtypes of JIA, representing excellent candidates as biomarkers for disease activity. Further studies are necessary to determine diagnostic value and correlations in other subtypes.

Novel biomarkers for prediction of outcome and therapeutic response in juvenile idiopathic arthritis

Introduction The search for biomarkers in juvenile idiopathic arthritis (JIA) is a promising and rapidly expanding field of investigation. The biomarkers identified so far may help to dissect the clinical heterogeneity of the illness, measure the level of disease activity, predict clinical remission, relapse, response to medications, course over time, complications, and forestall disease flares. Areas covered We provide a summary of the most recent advances in the development and application of biomarkers in JIA. We performed a PubMed search for significant articles combining predetermined keywords related to biomarkers in non-systemic and systemic JIA, chronic uveitis, and macrophage activation syndrome (MAS).The biomarkers available or under study are presented and discussed separately for non-systemic and systemic subtypes and for the two main disease complications, uveitis and MAS. Expert opinion The incorporation of valid and reliable biomarkers in standard clinical care may help to design better patient-tailored treatment regimens and to improve the therapeutic strategies based on the treat-to-target approach. The establishment of biomarkers that predict the risk of disease flare may lead to define the optimal modalities for treatment discontinuation after the achievement of clinical remission.

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis.

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis of childhood, characterized by various clinical phenotypes associated with variable prognosis. Significant progress has been achieved with the use of biologic treatments, which specifically block pro-inflammatory molecules involved in the disease pathogenesis. The most commonly used biologics in JIA are monoclonal antibodies and recombinant proteins targeting interleukins 1 (IL-1) and 6 (IL-6), and tumor necrosis factor α (TNF-α). Several biomarkers have been investigated in JIA. Aims: To assess the level of evidence available regarding the role of biomarkers in JIA related to guiding clinical and therapeutic decisions, providing disease prognostic information, facilitating disease activity monitoring and assessing biologic treatment response in JIA, as well as propose new strategies for biologic therapy-related biomarker use in JIA. Methods: We searched PubMed for relevant literature using predefined key words corresponding to several categories of biomarkers to assess their role in predicting and assessing biologic treatment response and clinical remission in JIA. Results: We reviewed serological, cellular, genetic, transcriptomic and imaging biomarkers, to identify candidates that are both well-established and widely used, as well as newly investigated in JIA on biologic therapy. We evaluated their role in management of JIA as well as identified the unmet needs for new biomarker discovery and better clinical applications. Conclusion: Although there are no ideal biomarkers in JIA, we identified serological biomarkers with potential clinical utility. We propose strategies of combining biomarkers of response to biologics in JIA, as well as routine implementation of clinically acceptable imaging biomarkers for improved disease assessment performance.

Role of Biomarkers in Juvenile Idiopathic Arthritis

The aim of this review was to identify the utility of biomarkers used in the diagnosis and the monitoring and treatment of Juvenile idiopathic arthritis (JIA). JIA is a heterogeneous group of diseases characterized by arthritis of unknown etiology that lasts for at least 6 weeks, with onset before the age of 16 years. Unlike adult rheumatoid arthritis, JIA is a heterogeneous arthritis with different subtypes. The diagnosis of JIA is based on clinical evaluation and often involves ruling out other causes of arthritis. Many biomarkers have been studied or are under development to define the classifications of JIA, assess disease activity, predict disease course, treatment response, or the risk of relapse. The diagnostic and prognostic use of biomarkers in JIA could be applied differently depending on diverse subtypes or individuals. To obtain the best clinical outcomes in JIA, it is important to understand the pathophysiology of each JIA subtype and to select and use appropriate biomarkers. (J Rheum Dis 2020;27:233-240)

Synovial-Fluid miRNA Signature for Diagnosis of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatism in childhood; microRNAs (miRNAs) have been proposed as diagnostic biomarkers. Although joints are the primary targets for JIA, a synovial fluid-based miRNA signature has never been studied. We aim to identify miRNA biomarkers in JIA by comparing synovial fluid and serum samples from children with JIA and K. kingae septic arthritis (SA). With next-generation high-throughput sequencing, we measured the absolute levels of 2083 miRNAs in synovial fluid and serum from an exploratory cohort of children and validated differentially expressed miRNAs in a replication study by using RT-qPCR. We identified a 19-miRNA signature only in synovial fluid samples that was significantly deregulated, with at least 2-fold change in expression, in JIA versus SA (p < 0.01). The combination of miR-6764-5p, miR-155, and miR-146a-5p expression in synovial fluid yielded an area under the receiver operating characteristic curve of 1 (95% CI 0.978 to 1), thereby perfectly differentiating JIA from SA in children. We propose, for the first time, a synovial fluid-specific miRNA signature for JIA and associated signaling pathways that may indicate potential biomarkers to assist in the classification and differential diagnosis of JIA and help in understanding JIA pathogenesis.

Juvenile idiopathic arthritis patients have a distinct cartilage and bone biomarker profile that differs from healthy and knee-injured children

Joint destruction is a hallmark of juvenile idiopathic arthritis (JIA). Clinical evaluation and radiographic imaging are current methods to identify destruction. Biomarkers could aid an earlier and more sensitive diagnosis. Our aim was to investigate levels of bone and cartilage degradation biomarkers in JIA patients, compared to healthy children or juveniles with knee injuries. Triple-paired synovial fluid, plasma and urine samples from 29 JIA patients were compared to 61 plasma samples from healthy children and synovial fluid from 41 knee-injured juveniles. Cartilage biomarkers ARGS neoepitope of aggrecan (ARGS), cartilage oligomeric matrix protein (COMP), type II collagen epitope (C2C), bone biomarkers N-terminal type I collagen cross-linked telopeptide (NTX-I) and tartrate-resistant acid phosphatase 5b (TRAP5b) were analysed by immunoassays. Plasma levels of ARGS, C2C, COMP and TRAP5b were increased in JIA compared to healthy children. Compared to knee-injured juveniles, synovial fluid C2C and TRAP5b were increased in JIA, while ARGS and COMP were decreased. For JIA patients, local (synovial fluid) and systemic (plasma/urine) levels of bone biomarkers correlated positively; age correlated negatively to plasma levels of C2C and TRAP5b; no correlation was found between biomarkers and gender, affected joint count, disease duration or medication. Elevated levels of destruction biomarkers in JIA compared to healthy children indicate a potential to serve as clinical tools for destructive joint disease. High levels of TRAP5b, NTX-I and collagen II in JIA in contrast to more pronounced aggrecan and COMP degradation in juvenile knee injuries, suggests that JIA patients have a unique biomarker pattern, different from healthy and knee-injured children.

Limits of Peripheral Blood Mononuclear Cells for Gene Expression-Based Biomarkers in Juvenile Idiopathic Arthritis.

Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic disease conditions affecting children in the USA. As with many rheumatic diseases, there is growing interest in using genomic technologies to develop biomarkers for either diagnosis or to guide treatment (“personalized medicine”). Here, we explore the use of gene expression patterns in peripheral blood mononuclear cells (PBMC) as a first step approach to developing such biomarkers. Although PBMC carry many theoretical advantages for translational research, we have found that sample heterogeneity makes RNASeq on PBMC unsuitable as a first-step method for screening biomarker candidates in JIA. RNASeq studies of homogeneous cell populations are more likely to be useful and informative.

Sleep Fragmentation and Biomarkers in Juvenile Idiopathic Arthritis.

(1) To compare sleep (nighttime sleep duration and sleep efficiency) and sleep fragmentation (movement and fragmentation index), as measured by actigraphy, and symptoms (pain and fatigue) in 8- to 14-year-old children with polyarticular and extended oligoarticular juvenile idiopathic arthritis (JIA) and (2) to examine the associations between sleep fragmentation (movement and fragmentation index) and the calcium-binding protein biomarkers S100A12 and myeloid-related protein (MRP8/14). Participants included 40 children with extended oligoarticular (n = 15) or polyarticular (n = 25) JIA and their parents. Serum protein samples were obtained during routine rheumatology clinic visits. Children completed the PedsQL Multidimensional Fatigue Scale and daily pain and sleep diaries and wore actigraphy monitors for 9 consecutive days. Parents completed the Children's Sleep Habits Questionnaire (CSHQ). Of the 40 children, 68% scored above the CSHQ clinical cutoff score for sleep disturbances. Mean nighttime sleep duration was 7.5 hr, and mean sleep efficiency was 85.3%. Group differences were not found for nighttime sleep duration, sleep efficiency, movement and fragmentation index, or S100A12 and MRP8/14 protein concentrations. In a stepwise regression, medications, joint count, and movement and fragmentation index explained 21% of the variance in MRP8/14 concentration. Decreased nighttime sleep duration, poor sleep efficiency, and fragmented sleep were observed in our sample, regardless of JIA category. Sleep fragmentation was a significant predictor of MRP8/14 protein concentration. Additional research is needed to understand the interrelations among sleep fragmentation, effects of medication, and S100A12 and MRP8/14 protein biomarkers in JIA.

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.

Current Developments in the Use of Biomarkers for Juvenile Idiopathic Arthritis

Use of biomarkers in clinical practice has proved extremely valuable and is a rapidly expanding field. However, despite the huge potential of biomarkers, for juvenile idiopathic arthritis (JIA) there are currently no validated paediatric biomarkers available to help with setting up a more tailored approach on which drug choice could be based, to achieve remission early in the course of disease. Early remission reduces burden of disease, limits side effects from toxic and unnecessary medication, and, most importantly, enhances quality of life. Several studies have suggested promising biomarkers: these may be a protein, cellular component, mRNA, or genetic component, for example a single nucleotide polymorphism (SNP). Here we describe recent developments in the use of biomarkers for JIA and their potential to assist in management of disease by predicting disease phenotype, severity, progression, and response to treatment, and determining when patients have reached stable remission and can safely discontinue treatment.

PReS-FINAL-1016: Micro vesicles as a magnifying glass; uncovering potential biomarkers in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a common chronic inflammatory diseases in childhood. Despite remission as a result of a plethora of treatment techniques, the chronic and relapsing nature of the disease requires continuous treatment which causes adverse side effects. It is important to uncover a biomarker that can efficiently predict patient responses to therapy as well as determine if patients will progress or regress as a result of treatment. Micro vesicles are key messengers containing many immune signaling molecules including cytokines, molecules known to play a major role in JIA.

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA. Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two-dimensional gel electrophoresis for protein separation and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry and quadripole time-of-flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA). The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2-fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA. Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.