Pathogenesis Of Juvenile Idiopathic Arthritis Research Articles

Comprehensive analysis of juvenile idiopathic arthritis patients’ immune characteristics based on bulk and single-cell sequencing data

Comprehensive analysis of juvenile idiopathic arthritis patients’ immune characteristics based on bulk and single-cell sequencing data

Specific Features of Juvenile Idiopathic Arthritis Patients' Cytokine Profile.

Juvenile idiopathic arthritis (JIA) is a systemic autoimmune disease that affects the joints, leading to disability. Cytokines and signaling molecules expressed by the immune system cells play a key role in JIA pathogenesis. Understanding how their content changes during pathology development can open up new opportunities for its diagnosis and treatment. The blood plasma of 30 patients with JIA (14 males and 16 females with a mean age of 12.2 ± 4.1) and 20 relatively healthy individuals (10 males and 10 females with a mean age of 10.20 ± 5.85) was analyzed to determine the levels of cytokines using the MILLIPLEX® kit. An increase in interleukins (IL)-1α, 1β, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 17F, 22, and 27 and a decrease in IL-3 levels have been shown in patients with JIA. Levels of cytokines, which are important for B-cell activation and proliferation, are increased, while levels of T-cell activating factors remained similar to the control group. Based on our results, it can be assumed that the use of combination therapy aimed at inhibiting both nonspecific interleukins and cytokines that activate B-cells will be more effective for the treatment of JIA.

Etiological Theories of Juvenile Idiopathic Arthritis (JIA): A Narrative Review

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease. It can be classified by diverse clinical presentations across subtypes classified by inflammation, swelling, and pain. This review examines current perspectives on factors impacting JIA etiology and future areas of development. Genetic and environmental factors, including early-life nutrition (i.e. breastmilk), mode of infant delivery, antibiotic exposure, and infections have been proposed as etiological candidates in the literature. Various human leukocyte antigen (HLA) genes and non-HLA genes related to immune signaling are risk factors for specific JIA subtypes. The impact of infection on JIA development has also been examined; it remains unclear whether infection plays a protective or harmful role. Moreover, shorter durations of breastfeeding during childhood may be associated with an increased risk of JIA development, given that breast milk consumption favorably increases bifidobacterium, changes the composition of the microbiome, and increases microbial diversity. Additionally, mode of delivery can play a role in the onset of JIA as birth delivery through Cesarean section puts children at a higher risk of JIA compared to infants born vaginally. Lastly, antibiotic exposure and its dose- and timedependent relationship also play a role in the microbiome and JIA pathogenesis. This research is significant, as an increased understanding of the etiology of clinically heterogeneous JIA subtypes may improve future treatments. Current limitations, research gaps, and future directions in the field are also discussed.

IL12B and IL17 genes polymorphisms associated with differential susceptibility to juvenile idiopathic arthritis and juvenile-onset systemic lupus erythematosus in Chinese children

Genetic factors play a crucial role in the immune response of juvenile idiopathic arthritis (JIA) and juvenile-onset systemic lupus erythematosus (JSLE). This study aimed to investigate the association of IL12B (rs3212227, rs6887695) and IL17 (rs2275913, rs763780) gene polymorphisms with the susceptibility of JIA and JSLE in Chinese children. A total of 303 healthy controls and 304 patients including 160 JIA and 144 patients were analyzed, and the genetic polymorphisms were genotyped by using a Sequenom MassArray system. There was a significant association between the IL12B rs3212227 genotype and the increased risk of JSLE (P = .01). For rs6887695, the minor allele C was significantly associated with the increased risk of JIA (odds ratio = 1.48, 95% confidence interval [CI] = 1.12–1.95, P = .005). Moreover, rs6887695 genotype was significantly associated with both JIA and JSLE susceptibility (P < .05). Besides, IL12B haplotype GC significantly associated with the increased risk of JIA (P = .016). However, no significant difference was found between the IL17 (rs2275913, rs763780) gene polymorphisms and JIA or JSLE susceptibility (P > .05). And similar genotype distributions of IL12B and IL17 polymorphisms were found between the patients with nephritis and without nephritis in JSLE (P > .05). Our results indicated that IL12B polymorphisms was associated with an increased risk for the development of JIA and JSLE in Chinese children, highlighting the involvement of inflammation in the pathogenesis of JIA and JSLE. Moreover, there was a risk haplotype in IL12B which could increase the risk of JIA.

Antibiotic exposure in prenatal and early life and risk of juvenile idiopathic arthritis: a nationwide register-based cohort study

ObjectivesEarly antibiotic exposure influences the gut microbiota which is believed to be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). We aimed to investigate the association between systemic antibiotics...

Infant gut microbiota and environment associate with juvenile idiopathic arthritis many years prior to disease onset, especially in genetically vulnerable children.

The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk. Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n=17,055), 111 of whom later acquired JIA (ABISJIA). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed. ABISJIA had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abundance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (q's<0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR=6.7; 1.81-24.84, p=0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition. Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis. Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linköping.

Juvenile Idiopathic Arthritis (JIA) Transitional Care Systems Require Revision to Improve Patient Outcomes: Opinion Review

Juvenile Idiopathic Arthritis (JIA), encompassing a class of arthritis for which there is no known origin, is the most common chronic inflammatory rheumatic condition arising during childhood. It is associated with a diverse host of complications resulting from immune and growth dysregulation characteristic of JIA pathogenesis. Past evidence has shown that care of JIA patients as they transition into adulthood — whether it be psychological, rheumatological, etc. — has been significantly and systemically overlooked. Patients have reported feeling increasingly overwhelmed, unprepared, and dismissed during this time of care. Therefore, improving pediatric patients’ experiences, as they navigate transition readiness into the adult healthcare system is a prevalent issue. This report aims to provide evidence on JIA-specific institutional barriers to a successful transitional care experience into adulthood in multiple comparator jurisdictions. This investigation, which analyzed both qualitative and quantitative evidence, revealed that major obstructions to constructive transitional care experiences include: flaws in JIA classification and diagnosis, lack of critical skill building pre-transition, insufficient patient education on their condition, and absence of adult healthcare provider support post-transition. Despite major limitations existing within transitional care provision, there are a variety of successful frameworks that warrant more attention and analysis. Consequently, future directions should focus on these effective models for guidance in order to improve transitional care resources and services, and better support JIA patients.

Juvenile idiopathic arthritis-associated genetic loci exhibit spatially constrained gene regulatory effects across multiple tissues and immune cell types

Juvenile idiopathic arthritis (JIA) is an autoimmune, inflammatory joint disease with complex genetic etiology. Previous GWAS have found many genetic loci associated with JIA. However, the biological mechanism behind JIA remains unknown mainly because most risk loci are located in non-coding genetic regions. Interestingly, increasing evidence has found that regulatory elements in the non-coding regions can regulate the expression of distant target genes through spatial (physical) interactions. Here, we used information on the 3D genome organization (Hi-C data) to identify target genes that physically interact with SNPs within JIA risk loci. Subsequent analysis of these SNP-gene pairs using data from tissue and immune cell type-specific expression quantitative trait loci (eQTL) databases allowed the identification of risk loci that regulate the expression of their target genes. In total, we identified 59 JIA-risk loci that regulate the expression of 210 target genes across diverse tissues and immune cell types. Functional annotation of spatial eQTLs within JIA risk loci identified significant overlap with gene regulatory elements (i.e., enhancers and transcription factor binding sites). We found target genes involved in immune-related pathways such as antigen processing and presentation (e.g., ERAP2, HLA class I and II), the release of pro-inflammatory cytokines (e.g., LTBR, TYK2), proliferation and differentiation of specific immune cell types (e.g., AURKA in Th17 cells), and genes involved in physiological mechanisms related to pathological joint inflammation (e.g., LRG1 in arteries). Notably, many of the tissues where JIA-risk loci act as spatial eQTLs are not classically considered central to JIA pathology. Overall, our findings highlight the potential tissue and immune cell type-specific regulatory changes contributing to JIA pathogenesis. Future integration of our data with clinical studies can contribute to the development of improved JIA therapy.

The plasma levels of Dickkopf-1 elevated in patients with Juvenile Idiopathic Arthritis.

To explore the role of two major inhibitors of Wnt signal pathway, Dickkopf-1(DKK-1) and Sclerostin (SOST), in the pathogenesis of juvenile idiopathic arthritis (JIA). 88 patients with JIA, which including 49 patients with enthesitis-related arthritis (ERA), 21 oligoarthritis (oJIA) and 18 polyarthritis (pJIA), and 36 age-and sex-matched children as healthy controls (HC) were enrolled in this study. The plasma levels of DKK-1 and SOST, measured using commercially available ELISA kits, were analyzed the correlation between the levels of DKK-1/SOST and JIA, and were analyzed in 14 patients with JIA during before and after treatment. Plasma levels of DKK-1 were significantly higher in the patients with JIA than that in HC, the elevation of DKK-1 level was positively correlated with HLA-B27 positive JIA. DKK-1 levels dropped significantly in patient with JIA after treatment (P < 0.05). There was no significant change in SOST levels among different subtypes of JIA, patients with JIA during before and after treatment, and HC. It was suggested that the DKK-1 may have a certain correlation with the pathogenesis of JIA, and DKK-1 levels are more closely related to the HLA-B27 positive-ERA. The abnormally elevated levels of Dickkopf-1 (DKK-1) may be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). DKK-1 levels were more closely related to the HLA-B27 positive-enthesitis-related arthritis (ERA). DKK-1 is an inhibitor of Wnt signaling pathway that promotes osteoblastic new bone formation; it is very rare for pediatric patients with HLA-B27 positive-ERA to manifest typical spondylitis, while sacroiliac arthritis is relatively common, which may be related to the high levels of DKK-1, which is consistent with the early stage of ankylosing spondylitis (AS).

Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.

Normal neonatal TREC and KREC levels in early onset juvenile idiopathic arthritis

Dysregulated central tolerance predisposes to autoimmune diseases. Reduced thymic output as well as compromised central B cell tolerance checkpoints have been proposed in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate neonatal levels of T-cell receptor excision circles (TRECs) and kappa-deleting element excision circles (KRECs), as markers of T- and B-cell output at birth, in patients with early onset JIA. TRECs and KRECs were quantitated by multiplex qPCR from dried blood spots (DBS), collected 2-5days after birth, in 156 children with early onset JIA and in 312 matched controls. When analysed from neonatal dried blood spots, the median TREC level was 78 (IQR 55-113) in JIA cases and 88 (IQR 57-117) copies/well in controls. The median KREC level was 51 (IQR 35-69) and 53 (IQR 35-74) copies/well, in JIA cases and controls, respectively. Stratification by sex and age at disease onset did not reveal any difference in the levels of TRECs and KRECs. T- and B-cell output at birth, as measured by TREC and KREC levels in neonatal dried blood spots, does not differ in children with early onset JIA compared to controls.

Aberrant Naive CD4-Positive T Cell Differentiation in Systemic Juvenile Idiopathic Arthritis Committed to B Cell Help.

Systemic juvenile idiopathic arthritis (JIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. In this study, we hypothesized that aberrant or incomplete polarization of T helper cells contributes to disease pathology. Cells or serum samples were obtained from healthy controls (n=72) and systemic JIA patients (n=171). Isolated naive T helper cells were cultured under Th1, Th17, and T follicular helper (Tfh) or T peripheral helper (Tph)-polarizing conditions and were partly cocultured with allogenic memory B cells. Cell samples were then analyzed for surface marker, transcription factor, and cytokine expression, as well as plasmablast generation. Serum samples were subjected to multiplexed bead and self-antigen arrays and enzyme-linked immunosorbent assays, and all data were compared to retrospective RNA profiling analyses. Differentiation of systemic JIA-naive T helper cells toward Th1 cells resulted in low expression levels of interferon-γ (IFNγ) and eomesodermin, which was associated in part with disease duration. In contrast, developing Th1 cells in patients with systemic JIA were found to produce elevated levels of interleukin-21 (IL-21), which negatively correlated with cellular expression of IFNγ and eomesodermin. In both in vitro and ex vivo analyses, IL-21 together with programmed cell death 1 (PD-1), inducible T cell costimulator (ICOS), and CXCR5 expression induced naive T helper cells from systemic JIA patients to polarize toward a Tfh/Tph cell phenotype. Retrospective analysis of whole-blood RNA-sequencing data demonstrated that Bcl-6, a master transcription factor in Tfh/Tph cell differentiation, was overexpressed specifically in patients with systemic JIA. Naive T helper cells from systemic JIA patients which were stimulated in vitro promoted B cellular plasmablast generation, and self-antigen array data indicated that IgG reactivity profiles of patients with systemic JIA differed from those of healthy controls. In the pathogenesis of systemic JIA, skewing of naive T helper cell differentiation toward a Tfh/Tph cell phenotype may represent an echo of autoimmunity, which may indicate the mechanisms driving progression toward chronic destructive arthritis.

[A preliminary study on the role of V-domain Ig suppressor of T cell activation in juvenile idiopathic arthritis].

To study the expression of V-domain Ig suppressor of T cell activation (VISTA) in peripheral blood of children with juvenile idiopathic arthritis (JIA) and its role in the pathogenesis of JIA. In this prospective study, peripheral blood was collected from 47 children with different subtypes of JIA and 10 healthy children. Flow cytometry was used to measure the expression levels of VISTA, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on CD14+ mononuclear cells, CD4+ T lymphocytes, and CD8+ T lymphocytes. The children with JIA had a significantly lower expression level of VISTA than the healthy children (P<0.05). There was a significant difference in the expression of VISTA between the children with different subtypes of JIA, with the lowest expression level in those with systemic JIA (P<0.05). There was also a significant difference in the expression of VISTA between different immune cells, with a significantly higher expression level on the surface of monocytes (P<0.05). Correlation analysis showed that VISTA was negatively correlated with the expression of IFN-γ and TNF-α on CD4+ T cells (r=-0.436 and -0.382 respectively, P<0.05), CD8+ T cells (r=-0.348 and -0.487 respectively, P<0.05), and CD14+ mononuclear cells (r=-0.582 and -0.603 respectively, P<0.05). The insufficient expression of VISTA may be associated with the pathogenesis of JIA, and enhancing the immunomodulatory effect of VISTA might be one option for the treatment of JIA in the future.

Calcium homeostasis and certain aspects of its disturbances in juvenile idiopathic arthritis

Background. In the pathogenesis of juvenile idiopathic arthritis (JIA), the main role is played by immunopathological changes in the body with a loss of tolerance to the elements of own tissues; herewith, disorders of calcium and bone metabolism are very important. Such changes occur as a result of autoimmune inflammation, pharmacotherapy, and the influence of a number of other factors that negatively affect calcium homeostasis in the body. Purpose: to study the features of calcium homeostasis and certain aspects of its disorders with an assessment of the structural and functional state of bone tissue, taking into account clinical subtypes and disease activity. Material and methods. Sixty-two children with JIA aged 3.5 to 16 years were examined, of them 11 had systemic and 51 had oligo- and polyarthritis. There were determined serum concentrations of a total calcium using the Lachema test kit (Czech Republic), protein-bound and ultrafiltered fractions, content of inorganic phosphorus (with the generally accepted spectrophotometric method using the Cobas 6000 analyzer and test systems by Roche Diagnostics, Switzerland), the activity of total alkaline phosphatase and its isoenzymes (bone and intestinal) using the Lachema test system (Czech Republic). Ultrasonic osteometry of the calcaneal (trabecular) bone was performed on the Achilles device (Lunar, USA). Results. A significant decrease was found in the average concentration of total calcium, protein-bound calcium in systemic JIA and in high disease activity. The concentration of the ultrafiltered calcium fraction decreased only with high disease activity. The average concentration of inorganic phosphorus in children with oligo- and polyarthritis was within the normal range, while in systemic JIA it decreased. A significant decrease in the serum content of inorganic phosphorus, as well as in the activity of total alkaline phosphatase and its bone isoenzyme was detected in patients with high activity of systemic JIA. In patients with JIA (oligo-, polyarthritis) characterized by a slowly progressive rheumatic process, only the indicator of broadband ultrasound attenuation significantly changed during the first year of the disease, while the speed of ultrasound propagation and the index of bone tissue strength were not changed. In patients with a longer duration of the disease, all densitometric indicators decreased significantly. In the group of patients with systemic JIA and a rapidly progressive course, high activity of the disease that required a glucocorticoid therapy, a significant loss of bone mass was noted by the end of the first year of the disease. Conclusions. In JIA, there are changes in the concentration of total calcium and its protein-bound and ultrafiltered fractions in the blood serum, which indicate the tension of calcium-phosphorus metabolism and possible calcium deficiency in the body already at the early stages of the pathological process. A decrease in the activity of the alkaline phosphatase and its bone isoenzyme is associated with a violation of the structural and functional changes in the bone system of patients with JIA, which progresses with the duration of the disease. Patients with JIA require timely diagnosis and monitoring of calcium-phosphorus metabolism disorders with an assessment of the structural and functional state of the bone system for purposeful correction of comprehensive therapy due to the use of drugs in order to increase bone tissue regeneration, reduce the progression of osteopenia and osteoporosis, and preserve the health of the growing organism.

The Role of Interleukin-17 in Juvenile Idiopathic Arthritis: From Pathogenesis to Treatment.

Background and Objectives: Interleukin-17 (IL-17) is a cytokine family consisting of six members and five specific receptors. IL-17A was the first member to be identified in 1993. Since then, several studies have elucidated that IL-17 has predominantly pro-inflammatory activity and that its production is involved in both the defense against pathogens and the genesis of autoimmune processes. Materials and Methods: In this review, we provide an overview of the role of interleukin-17 in the pathogenesis of juvenile idiopathic arthritis (JIA) and its relationship with IL-23, the so-called IL-23-IL-17 axis, by reporting updated findings from the scientific literature. Results: Strong evidence supports the role of interleukin-17A in the pathogenesis of JIA after the deregulated production of this interleukin by both T helper 17 (Th17) cells and cells of innate immunity. The blocking of IL-17A was found to improve the course of JIA, leading to the approval of the use of the human anti-IL17A monoclonal antibody secukinumab in the treatment of the JIA subtypes juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA). Conclusions: IL-17A plays a central role in the pathogenesis of JIA. Blocking its production with specific biologic drugs enables the effective treatment of this disabling childhood rheumatic disease.

HLA-DRB typing among polyarticular juvenile idiopathic arthritis and progressive pseudorheumatoid dysplasia patients

Juvenile Idiopathic Arthritis (JIA) is a multi-factorial disease influenced both by environmental and genetic factors. Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disorder affecting multiple joints, mimicking JIA. Aim of the work: to reveal the frequency of HLA-DR types among the studied patients and to correlate the different allele variations clinically. Patients and methods: Thirty JIA patients, in addition to 15 molecularly diagnosed PPD patients were subjected to full history taking and clinical examination. HLA-DRB1 typing was performed to 24/30 JIA and 12/15 PPD cases and thirty healthy age and sex matched children who were included as a control group. Results: The JIA patients were 22 females and 8 males with mean age of 15.8 ± 1.96 years and disease duration 5.3 ± 4.4 years. PPD patients were 8 males and 7 females with mean age of 8.7 ± 3.06 years and disease duration 3.95 ± 2.68 years. A significant frequency of HLA-DRB 04 (p = 0.049) among JIA patients was present in comparison to the controls (OR = 2.81, CI:1.02–7.75), other risky alleles were HLA-DRB 10, 13 and 15. However, HLA-DRB 01, 03, 07, 11 and 14 were found to be protective. HLA-DRB 01, 04, 10 and 13 were found to be risky alleles in PPD. However, HLA 03, 07, 11 and 15 were found to be protective alleles among PPD patients. Conclusion: HLA-DRB 04 was found in a higher frequency in JIA patients with a significant difference in comparison to the controls, denoting that it may play a role in the genetic pathogenesis of JIA.

Mitigated suppressive function of regulatory T cells (Treg) upon Th17-inducing cytokines in oligo- and polyarticular Juvenile Idiopathic Arthritis (JIA) patients

BackgroundThe plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients.MethodsTh17 and Treg characteristics of CD4+ helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4+CD25+CD127− cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays.ResultsOur findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function.ConclusionsOur results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients.

B Cells on the Stage of Inflammation in Juvenile Idiopathic Arthritis: Leading or Supporting Actors in Disease Pathogenesis?

Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.

Research progress in drug therapy of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. With the gradual expansion of the incidence of JIA in the population, the pathogenesis and treatment of JIA were further explored and analyzed, and JIA has achieved some success in drug therapy. A systemic literature search was conducted on PubMed, Cochrane Library, EMBASE, ISI Web of Science, the US National Institutes of Health Ongoing Trials Register, and the EU Clinical Trials Register. Through the searching of clinical trials of JIA in recent years, we summarized the progress of the clinical treatment of JIA. The main treatment drugs for JIA include non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs and biological agents. So far, a variety of biological agents targeting the cytokines and receptors involved in its pathogenesis have been gradually approved for JIA in many countries. The application of biological agents in JIA showed good efficacy and safety, bringing unprecedented experience to children and adolescents with JIA. The potential and advantages of biologic agents in the treatment of JIA are significant, and the application of biologic agents in the treatment of JIA will be more and more common.

Complement Activation Profiles in Patients with Juvenile Idiopathic Arthritis

Objectives: Besides T- and B-cells also the innate immunity is playing an effective role in the pathogenesis of Juvenile idiopathic arthritis (JIA) reported in literature. The complement system (CS) is activated by the three different ways classical pathway (CP), lectin pathway (LP) and alternative pathway (AP). This is a controlled prospective observational single center study focused on the three pathways of CS and its effector, the terminal complement complex (TCC), associated with disease activity in all clinical JIA subgroups. Methods: Peripheral blood (PB) samples (n=159) of 60 JIA patients (partially also longitudinal visits) were analyzed for specific complement pathway activation (COMPL300 ELISA), complement factor H (CFH)-autoantibodies (CFHAb ELISA), and the soluble TCC (sC5b-9 ELISA) in serum (S) and EDTA plasma (P). TCC was also analyzed in synovial fluid (SF) of JIA patients (n=9) controlled with samples of healthy adults (n=12) obtained by arthroscopy (primarily gonarthrosis). As healthy controls (HC) adults (n=100) and children (n=18) without inflammatory diseases were tested. The JADAS10 defined the acute phase of the disease. Results: We compared the elevated serum TCC levels of JIA patients in the acute phase of the disease (13.32 IQR 8.09-19.48; p&lt;0,001) with the controls' levels (7.78 IQR 4.93-10.31). Subgroup analyses showed statistically significant (s.s.) elevation in PArf+, OAper, and OAext. COMPL300 analyses revealed that JIA patients with acute disease had lower CP (82% IQR 37-97% vs 105% IQR 98-115%; p&lt;0.001), LP (31% IQR 2-86% vs 80% IQR 20-101%; p&lt;0.001), and AP (25% IQR 2-88% vs 85% IQR 70-98%; p&lt;0.001) capacity compared to the HC average due to chronic activation in all three pathways. Both TCC and COMPL300 analyses during acute phase and remission showed a clear tendency, especially in PArf+ but only s.s. in the individual course. Remarkable sJIA patients neither in TCC nor in COMPL300 analyses showed complement activation. No evidence of CFH-autoantibodies was found in our study group. The TCC levels in SF showed a median of 2.48 IQR 1.71-2.76 AU/ml in JIA patients and surprisingly high levels in HC with 6.7 IQR 3.9-9.24 AU/ml. Conclusion: Specific subgroups of JIA patients (extOA, PARf+, ERA) showed increased CS activation in TCC in PB in the acute course of the disease. Furthermore, the decreased CS capacity, especially in the CP and AP, confirms the consumption of complement components as an additional contributor to the disease pathogenesis and acute course. Due to the CS activation throughout all disease activity states, we could not determine s.s. between the acute and remission phases in our cohort. However, COMPL300 in combination with TCC seems to be a helpful acute disease biomarker in the individual course. The pharmacological modulation of CS components might be a valid alternative approach in treatmentresistant patients, although further investigations are needed.